Maya M. Kasowski

All Publications

• Peanut allergy oral immunotherapy drives single-cell multi-omic changes in peanut-reactive T cells associated with sustained unresponsiveness. Nature immunology Han, X., Skatova, V., Mikelov, A., Ji, X., Hoh, R. A., Lee, J. Y., Cao, S., Seastedt, H., Schuetz, J., Fernandes, A., Singhal, A., Grubert, F., DeKruyff, R. H., Maecker, H. T., Galli, S. J., Manohar, M., Chinthrajah, R. S., Kasowski, M. M., Boyd, S. D., Nadeau, K. C. 2025

  Abstract

  Oral immunotherapy (OIT) is the only U.S. Food and Drud Administration-approved treatment for peanut allergy. Peanut-reactive (pr) CD4+ T cells are pivotal in peanut allergy pathogenesis and OIT-induced desensitization. However, the underlying pr CD4+ T cell immune mechanisms leading to sustained unresponsiveness after OIT discontinuation are largely unknown. We analyzed single-cell RNA and protein immunophenotypes and T cell receptor repertoires of pr CD4+ T cells from a phase 2 peanut OIT trial cohort. We identified increased cytotoxicity-related phenotypes and type 1 helper cytotoxic T lymphocyte-like cell clonal expansion during OIT, while type 2 helper T (TH2) cell-related phenotypes and TH2-like cell clonal expansion decreased. OIT participants achieving sustained unresponsiveness were distinguished by lower baseline TH2-related phenotypes, elevated post-OIT cytotoxicity-related pr effector T cell gene signatures and higher CD39 expression in pr regulatory T cells. These findings clarify OIT-induced CD4+ T cell tolerance mechanisms and can guide effective allergen-specific OIT strategies.

  View details for DOI 10.1038/s41590-025-02323-3

  View details for PubMedID 41188408

  View details for PubMedCentralID 7223701

• Deep learning-based cell type profiles reveal signatures of Alzheimer's disease resilience and resistance. Brain : a journal of neurology Berson, E., Perna, A., Bukhari, S., Kim, Y., Xue, L., Seong, D., Mataraso, S., Ghanem, M., Chang, A. L., Montine, K. S., Keene, C. D., Kasowski, M., Aghaeepour, N., Montine, T. J. 2025

  Abstract

  Neurological disorders result from the complex and poorly understood contributions of many cell types, essential for uncovering mechanisms behind these disorders and identifying specific therapeutic targets. Single-nucleus technologies have advanced brain disease research, but remain limited by their low nuclear transcriptional coverage, high cost, and technical complexity. To address this, we applied a transformer-based deep learning model that restores cell type-specific investigation transcriptional programs from bulk RNA-seq, significantly outperforming previous methods. This enables large-scale and cost-effective investigation of cell type-specific transcriptomes in complex and heterogeneous phenotypes such as cognitive resilience or brain resistance to Alzheimer's disease. Our analysis identified astrocytes as the major cell mediator of Alzheimer's disease resilience across cerebral cortex regions, while excitatory neurons and oligodendrocyte progenitor cells emerged as the major cell mediators of resistance, maintaining synaptic function and preserving neuron health. Finally, we show that our approach could restore the whole tissue transcriptome, offering an unbiased framework for exploring cell-specific functions beyond single nucleus data.

  View details for DOI 10.1093/brain/awaf285

  View details for PubMedID 40794555

• DART-Eval: A Comprehensive DNA Language Model Evaluation Benchmark on Regulatory DNA. ArXiv Patel, A., Singhal, A., Wang, A., Pampari, A., Kasowski, M., Kundaje, A. 2025

  Abstract

  Recent advances in self-supervised models for natural language, vision, and protein sequences have catalyzed the development of genomic DNA language models (DNALMs). These models aim to learn generalizable representations of diverse DNA elements, potentially enabling various downstream genomic prediction, interpretation and design tasks. However, existing benchmarks do not adequately assess the capabilities of DNALMs on an important class of non-coding DNA elements critical for regulating gene activity. Here, we introduce DART-Eval, a suite of representative benchmarks focused on regulatory DNA to evaluate performance of DNALMs across zero-shot, probed, and fine-tuned settings against contemporary ab initio models as baselines. DART-Eval addresses biologically relevant tasks including sequence motif discovery, cell-type specific regulatory activity prediction, and counterfactual prediction of regulatory genetic variants. Our systematic evaluations reveal that current annotation-agnostic DNALMs exhibit inconsistent performance and do not offer compelling gains over alternative baseline models for most tasks, despite requiring significantly more computational resources. We discuss potentially promising modeling, data curation, and evaluation strategies for the next generation of DNALMs. Our benchmark datasets and evaluation framework are available at https://github.com/kundajelab/DART-Eval.

  View details for PubMedID 40799805

• DART-Eval: A Comprehensive DNA Language Model Evaluation Benchmark on Regulatory DNA. ArXiv Patel, A., Singhal, A., Wang, A., Pampari, A., Kasowski, M., Kundaje, A. 2025

  Abstract

  Recent advances in self-supervised models for natural language, vision, and protein sequences have catalyzed the development of genomic DNA language models (DNALMs). These models aim to learn generalizable representations of diverse DNA elements, potentially enabling various downstream genomic prediction, interpretation and design tasks. However, existing benchmarks do not adequately assess the capabilities of DNALMs on an important class of non-coding DNA elements critical for regulating gene activity. Here, we introduce DART-Eval, a suite of representative benchmarks focused on regulatory DNA to evaluate performance of DNALMs across zero-shot, probed, and fine-tuned settings against contemporary ab initio models as baselines. DART-Eval addresses biologically relevant tasks including sequence motif discovery, cell-type specific regulatory activity prediction, and counterfactual prediction of regulatory genetic variants. Our systematic evaluations reveal that current annotation-agnostic DNALMs exhibit inconsistent performance and do not offer compelling gains over alternative baseline models for most tasks, despite requiring significantly more computational resources. We discuss potentially promising modeling, data curation, and evaluation strategies for the next generation of DNALMs. Our benchmark datasets and evaluation framework are available at https://github.com/kundajelab/DART-Eval.

  View details for PubMedID 40799805

  View details for PubMedCentralID PMC12340898

• Applications of Metabolomics and Lipidomics in the Neonatal Intensive Care Unit. NeoReviews Reiss, J. D., Mataraso, S. J., Holzapfel, L. F., Marić, I., Kasowski, M. M., Martin, C. R., Long, J. Z., Stevenson, D. K., Shaw, G. M. 2025; 26 (2): e100-e114

  Abstract

  The metabolome and lipidome comprise the thousands of molecular compounds in an organism. Molecular compounds consist of the upstream metabolic components of intracellular reactions or the byproducts of cellular pathways. Molecular and biochemical perturbations are associated with disorders in newborns and infants. The diagnosis of inborn errors of metabolism has relied on targeted metabolomics for several decades. Newer approaches offer the potential to identify novel biomarkers for common diseases of the newborn and infant. They may also elucidate novel predictive or diagnostic measures for a variety of health trajectories. Here, we review the relevance of the metabolome and lipidome for common disorders and highlight challenges and opportunities for future investigations.

  View details for DOI 10.1542/neo.26-2-011

  View details for PubMedID 39889768

• Deep Learning the Cis-Regulatory Code of Epigenomic Rewiring By Fusion Transcription Factors in Pediatric Leukemia Mani, S., Grubert, F., Gratzinger, D., Kundaje, A., Kasowski, M. ELSEVIER. 2024: 4993

  View details for DOI 10.1182/blood-2024-209601

  View details for Web of Science ID 001407948200003

• GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency. Nature communications Guerrero, J. A., Klysz, D. D., Chen, Y., Malipatlolla, M., Lone, J., Fowler, C., Stuani, L., May, A., Bashti, M., Xu, P., Huang, J., Michael, B., Contrepois, K., Dhingra, S., Fisher, C., Svensson, K. J., Davis, K. L., Kasowski, M., Feldman, S. A., Sotillo, E., Mackall, C. L. 2024; 15 (1): 8658

  Abstract

  The intensive nutrient requirements needed to sustain T cell activation and proliferation, combined with competition for nutrients within the tumor microenvironment, raise the prospect that glucose availability may limit CAR-T cell function. Here, we seek to test the hypothesis that stable overexpression (OE) of the glucose transporter GLUT1 in primary human CAR-T cells would improve their function and antitumor potency. We observe that GLUT1OE in CAR-T cells increases glucose consumption, glycolysis, glycolytic reserve, and oxidative phosphorylation, and these effects are associated with decreased T cell exhaustion and increased Th17 differentiation. GLUT1OE also induces broad metabolic reprogramming associated with increased glutathione-mediated resistance to reactive oxygen species, and increased inosine accumulation. When challenged with tumors, GLUT1OE CAR-T cells secrete more proinflammatory cytokines and show enhanced cytotoxicity in vitro, and demonstrate superior tumor control and persistence in mouse models. Our collective findings support a paradigm wherein glucose availability is rate limiting for effector CAR-T cell function and demonstrate that enhancing glucose availability via GLUT1OE could augment antitumor immune function.

  View details for DOI 10.1038/s41467-024-52666-y

  View details for PubMedID 39370422

  View details for PubMedCentralID PMC11456602

• Deciphering the impact of genomic variation on function. Nature 2024; 633 (8028): 47-57

  Abstract

  Our genomes influence nearly every aspect of human biology-from molecular and cellular functions to phenotypes in health and disease. Studying the differences in DNA sequence between individuals (genomic variation) could reveal previously unknown mechanisms of human biology, uncover the basis of genetic predispositions to diseases, and guide the development of new diagnostic tools and therapeutic agents. Yet, understanding how genomic variation alters genome function to influence phenotype has proved challenging. To unlock these insights, we need a systematic and comprehensive catalogue of genome function and the molecular and cellular effects of genomic variants. Towards this goal, the Impact of Genomic Variation on Function (IGVF) Consortium will combine approaches in single-cell mapping, genomic perturbations and predictive modelling to investigate the relationships among genomic variation, genome function and phenotypes. IGVF will create maps across hundreds of cell types and states describing how coding variants alter protein activity, how noncoding variants change the regulation of gene expression, and how such effects connect through gene-regulatory and protein-interaction networks. These experimental data, computational predictions and accompanying standards and pipelines will be integrated into an open resource that will catalyse community efforts to explore how our genomes influence biology and disease across populations.

  View details for DOI 10.1038/s41586-024-07510-0

  View details for PubMedID 39232149

  View details for PubMedCentralID 7405896

• Chromatin activity identifies differential gene regulation across human ancestries. Genome biology Pettie, K. P., Mumbach, M., Lea, A. J., Ayroles, J., Chang, H. Y., Kasowski, M., Fraser, H. B. 2024; 25 (1): 21

  Abstract

  Current evidence suggests that cis-regulatory elements controlling gene expression may be the predominant target of natural selection in humans and other species. Detecting selection acting on these elements is critical to understanding evolution but remains challenging because we do not know which mutations will affect gene regulation.To address this, we devise an approach to search for lineage-specific selection on three critical steps in transcriptional regulation: chromatin activity, transcription factor binding, and chromosomal looping. Applying this approach to lymphoblastoid cells from 831 individuals of either European or African descent, we find strong signals of differential chromatin activity linked to gene expression differences between ancestries in numerous contexts, but no evidence of functional differences in chromosomal looping. Moreover, we show that enhancers rather than promoters display the strongest signs of selection associated with sites of differential transcription factor binding.Overall, our study indicates that some cis-regulatory adaptation may be more easily detected at the level of chromatin than DNA sequence. This work provides a vast resource of genomic interaction data from diverse human populations and establishes a novel selection test that will benefit future study of regulatory evolution in humans and other species.

  View details for DOI 10.1186/s13059-024-03165-2

  View details for PubMedID 38225662

  View details for PubMedCentralID PMC10789071

• Author Correction: Perspectives on ENCODE. Nature ENCODE Project Consortium, Snyder, M. P., Gingeras, T. R., Moore, J. E., Weng, Z., Gerstein, M. B., Ren, B., Hardison, R. C., Stamatoyannopoulos, J. A., Graveley, B. R., Feingold, E. A., Pazin, M. J., Pagan, M., Gilchrist, D. A., Hitz, B. C., Cherry, J. M., Bernstein, B. E., Mendenhall, E. M., Zerbino, D. R., Frankish, A., Flicek, P., Myers, R. M., Abascal, F. B., Acosta, R., Addleman, N. J., Adrian, J., Afzal, V., Aken, B., Ai, R., Akiyama, J. A., Jammal, O. A., Amrhein, H., Anderson, S. M., Andrews, G. R., Antoshechkin, I., Ardlie, K. G., Armstrong, J., Astley, M., Banerjee, B., Barkal, A. A., Barnes, I. H., Barozzi, I., Barrell, D., Barson, G., Bates, D., Baymuradov, U. K., Bazile, C., Beer, M. A., Beik, S., Bender, M. A., Bennett, R., Bouvrette, L. P., Bernstein, B. E., Berry, A., Bhaskar, A., Bignell, A., Blue, S. M., Bodine, D. M., Boix, C., Boley, N., Borrman, T., Borsari, B., Boyle, A. P., Brandsmeier, L. A., Breschi, A., Bresnick, E. H., Brooks, J. A., Buckley, M., Burge, C. B., Byron, R., Cahill, E., Cai, L., Cao, L., Carty, M., Castanon, R. G., Castillo, A., Chaib, H., Chan, E. T., Chee, D. R., Chee, S., Chen, H., Chen, H., Chen, J., Chen, S., Cherry, J. M., Chhetri, S. B., Choudhary, J. S., Chrast, J., Chung, D., Clarke, D., Cody, N. A., Coppola, C. J., Coursen, J., D'Ippolito, A. M., Dalton, S., Danyko, C., Davidson, C., Davila-Velderrain, J., Davis, C. A., Dekker, J., Deran, A., DeSalvo, G., Despacio-Reyes, G., Dewey, C. N., Dickel, D. E., Diegel, M., Diekhans, M., Dileep, V., Ding, B., Djebali, S., Dobin, A., Dominguez, D., Donaldson, S., Drenkow, J., Dreszer, T. R., Drier, Y., Duff, M. O., Dunn, D., Eastman, C., Ecker, J. R., Edwards, M. D., El-Ali, N., Elhajjajy, S. I., Elkins, K., Emili, A., Epstein, C. B., Evans, R. C., Ezkurdia, I., Fan, K., Farnham, P. J., Farrell, N., Feingold, E. A., Ferreira, A., Fisher-Aylor, K., Fitzgerald, S., Flicek, P., Foo, C. S., Fortier, K., Frankish, A., Freese, P., Fu, S., Fu, X., Fu, Y., Fukuda-Yuzawa, Y., Fulciniti, M., Funnell, A. P., Gabdank, I., Galeev, T., Gao, M., Giron, C. G., Garvin, T. H., Gelboin-Burkhart, C. A., Georgolopoulos, G., Gerstein, M. B., Giardine, B. M., Gifford, D. K., Gilbert, D. M., Gilchrist, D. A., Gillespie, S., Gingeras, T. R., Gong, P., Gonzalez, A., Gonzalez, J. M., Good, P., Goren, A., Gorkin, D. U., Graveley, B. R., Gray, M., Greenblatt, J. F., Griffiths, E., Groudine, M. T., Grubert, F., Gu, M., Guigo, R., Guo, H., Guo, Y., Guo, Y., Gursoy, G., Gutierrez-Arcelus, M., Halow, J., Hardison, R. C., Hardy, M., Hariharan, M., Harmanci, A., Harrington, A., Harrow, J. L., Hashimoto, T. B., Hasz, R. D., Hatan, M., Haugen, E., Hayes, J. E., He, P., He, Y., Heidari, N., Hendrickson, D., Heuston, E. F., Hilton, J. A., Hitz, B. C., Hochman, A., Holgren, C., Hou, L., Hou, S., Hsiao, Y. E., Hsu, S., Huang, H., Hubbard, T. J., Huey, J., Hughes, T. R., Hunt, T., Ibarrientos, S., Issner, R., Iwata, M., Izuogu, O., Jaakkola, T., Jameel, N., Jansen, C., Jiang, L., Jiang, P., Johnson, A., Johnson, R., Jungreis, I., Kadaba, M., Kasowski, M., Kasparian, M., Kato, M., Kaul, R., Kawli, T., Kay, M., Keen, J. C., Keles, S., Keller, C. A., Kelley, D., Kellis, M., Kheradpour, P., Kim, D. S., Kirilusha, A., Klein, R. J., Knoechel, B., Kuan, S., Kulik, M. J., Kumar, S., Kundaje, A., Kutyavin, T., Lagarde, J., Lajoie, B. R., Lambert, N. J., Lazar, J., Lee, A. Y., Lee, D., Lee, E., Lee, J. W., Lee, K., Leslie, C. S., Levy, S., Li, B., Li, H., Li, N., Li, S., Li, X., Li, Y. I., Li, Y., Li, Y., Li, Y., Lian, J., Libbrecht, M. W., Lin, S., Lin, Y., Liu, D., Liu, J., Liu, P., Liu, T., Liu, X. S., Liu, Y., Liu, Y., Long, M., Lou, S., Loveland, J., Lu, A., Lu, Y., Lecuyer, E., Ma, L., Mackiewicz, M., Mannion, B. J., Mannstadt, M., Manthravadi, D., Marinov, G. K., Martin, F. J., Mattei, E., McCue, K., McEown, M., McVicker, G., Meadows, S. K., Meissner, A., Mendenhall, E. M., Messer, C. L., Meuleman, W., Meyer, C., Miller, S., Milton, M. G., Mishra, T., Moore, D. E., Moore, H. M., Moore, J. E., Moore, S. H., Moran, J., Mortazavi, A., Mudge, J. M., Munshi, N., Murad, R., Myers, R. M., Nandakumar, V., Nandi, P., Narasimha, A. M., Narayanan, A. K., Naughton, H., Navarro, F. C., Navas, P., Nazarovs, J., Nelson, J., Neph, S., Neri, F. J., Nery, J. R., Nesmith, A. R., Newberry, J. S., Newberry, K. M., Ngo, V., Nguyen, R., Nguyen, T. B., Nguyen, T., Nishida, A., Noble, W. S., Novak, C. S., Novoa, E. M., Nunez, B., O'Donnell, C. W., Olson, S., Onate, K. C., Otterman, E., Ozadam, H., Pagan, M., Palden, T., Pan, X., Park, Y., Partridge, E. C., Paten, B., Pauli-Behn, F., Pazin, M. J., Pei, B., Pennacchio, L. A., Perez, A. R., Perry, E. H., Pervouchine, D. D., Phalke, N. N., Pham, Q., Phanstiel, D. H., Plajzer-Frick, I., Pratt, G. A., Pratt, H. E., Preissl, S., Pritchard, J. K., Pritykin, Y., Purcaro, M. J., Qin, Q., Quinones-Valdez, G., Rabano, I., Radovani, E., Raj, A., Rajagopal, N., Ram, O., Ramirez, L., Ramirez, R. N., Rausch, D., Raychaudhuri, S., Raymond, J., Razavi, R., Reddy, T. E., Reimonn, T. M., Ren, B., Reymond, A., Reynolds, A., Rhie, S. K., Rinn, J., Rivera, M., Rivera-Mulia, J. C., Roberts, B., Rodriguez, J. M., Rozowsky, J., Ryan, R., Rynes, E., Salins, D. N., Sandstrom, R., Sasaki, T., Sathe, S., Savic, D., Scavelli, A., Scheiman, J., Schlaffner, C., Schloss, J. A., Schmitges, F. W., See, L. H., Sethi, A., Setty, M., Shafer, A., Shan, S., Sharon, E., Shen, Q., Shen, Y., Sherwood, R. I., Shi, M., Shin, S., Shoresh, N., Siebenthall, K., Sisu, C., Slifer, T., Sloan, C. A., Smith, A., Snetkova, V., Snyder, M. P., Spacek, D. V., Srinivasan, S., Srivas, R., Stamatoyannopoulos, G., Stamatoyannopoulos, J. A., Stanton, R., Steffan, D., Stehling-Sun, S., Strattan, J. S., Su, A., Sundararaman, B., Suner, M., Syed, T., Szynkarek, M., Tanaka, F. Y., Tenen, D., Teng, M., Thomas, J. A., Toffey, D., Tress, M. L., Trout, D. E., Trynka, G., Tsuji, J., Upchurch, S. A., Ursu, O., Uszczynska-Ratajczak, B., Uziel, M. C., Valencia, A., Biber, B. V., van der Velde, A. G., Van Nostrand, E. L., Vaydylevich, Y., Vazquez, J., Victorsen, A., Vielmetter, J., Vierstra, J., Visel, A., Vlasova, A., Vockley, C. M., Volpi, S., Vong, S., Wang, H., Wang, M., Wang, Q., Wang, R., Wang, T., Wang, W., Wang, X., Wang, Y., Watson, N. K., Wei, X., Wei, Z., Weisser, H., Weissman, S. M., Welch, R., Welikson, R. E., Weng, Z., Westra, H., Whitaker, J. W., White, C., White, K. P., Wildberg, A., Williams, B. A., Wine, D., Witt, H. N., Wold, B., Wolf, M., Wright, J., Xiao, R., Xiao, X., Xu, J., Xu, J., Yan, K., Yan, Y., Yang, H., Yang, X., Yang, Y., Yardimci, G. G., Yee, B. A., Yeo, G. W., Young, T., Yu, T., Yue, F., Zaleski, C., Zang, C., Zeng, H., Zeng, W., Zerbino, D. R., Zhai, J., Zhan, L., Zhan, Y., Zhang, B., Zhang, J., Zhang, J., Zhang, K., Zhang, L., Zhang, P., Zhang, Q., Zhang, X., Zhang, Y., Zhang, Z., Zhao, Y., Zheng, Y., Zhong, G., Zhou, X., Zhu, Y., Zimmerman, J. 2022

  View details for DOI 10.1038/s41586-021-04213-8

  View details for PubMedID 35474002

• Author Correction: Expanded encyclopaedias of DNA elements in the human and mouse genomes. Nature ENCODE Project Consortium, Moore, J. E., Purcaro, M. J., Pratt, H. E., Epstein, C. B., Shoresh, N., Adrian, J., Kawli, T., Davis, C. A., Dobin, A., Kaul, R., Halow, J., Van Nostrand, E. L., Freese, P., Gorkin, D. U., Shen, Y., He, Y., Mackiewicz, M., Pauli-Behn, F., Williams, B. A., Mortazavi, A., Keller, C. A., Zhang, X., Elhajjajy, S. I., Huey, J., Dickel, D. E., Snetkova, V., Wei, X., Wang, X., Rivera-Mulia, J. C., Rozowsky, J., Zhang, J., Chhetri, S. B., Zhang, J., Victorsen, A., White, K. P., Visel, A., Yeo, G. W., Burge, C. B., Lecuyer, E., Gilbert, D. M., Dekker, J., Rinn, J., Mendenhall, E. M., Ecker, J. R., Kellis, M., Klein, R. J., Noble, W. S., Kundaje, A., Guigo, R., Farnham, P. J., Cherry, J. M., Myers, R. M., Ren, B., Graveley, B. R., Gerstein, M. B., Pennacchio, L. A., Snyder, M. P., Bernstein, B. E., Wold, B., Hardison, R. C., Gingeras, T. R., Stamatoyannopoulos, J. A., Weng, Z., Abascal, F., Acosta, R., Addleman, N. J., Adrian, J., Afzal, V., Aken, B., Akiyama, J. A., Jammal, O. A., Amrhein, H., Anderson, S. M., Andrews, G. R., Antoshechkin, I., Ardlie, K. G., Armstrong, J., Astley, M., Banerjee, B., Barkal, A. A., Barnes, I. H., Barozzi, I., Barrell, D., Barson, G., Bates, D., Baymuradov, U. K., Bazile, C., Beer, M. A., Beik, S., Bender, M. A., Bennett, R., Bouvrette, L. P., Bernstein, B. E., Berry, A., Bhaskar, A., Bignell, A., Blue, S. M., Bodine, D. M., Boix, C., Boley, N., Borrman, T., Borsari, B., Boyle, A. P., Brandsmeier, L. A., Breschi, A., Bresnick, E. H., Brooks, J. A., Buckley, M., Burge, C. B., Byron, R., Cahill, E., Cai, L., Cao, L., Carty, M., Castanon, R. G., Castillo, A., Chaib, H., Chan, E. T., Chee, D. R., Chee, S., Chen, H., Chen, H., Chen, J., Chen, S., Cherry, J. M., Chhetri, S. B., Choudhary, J. S., Chrast, J., Chung, D., Clarke, D., Cody, N. A., Coppola, C. J., Coursen, J., D'Ippolito, A. M., Dalton, S., Danyko, C., Davidson, C., Davila-Velderrain, J., Davis, C. A., Dekker, J., Deran, A., DeSalvo, G., Despacio-Reyes, G., Dewey, C. N., Dickel, D. E., Diegel, M., Diekhans, M., Dileep, V., Ding, B., Djebali, S., Dobin, A., Dominguez, D., Donaldson, S., Drenkow, J., Dreszer, T. R., Drier, Y., Duff, M. O., Dunn, D., Eastman, C., Ecker, J. R., Edwards, M. D., El-Ali, N., Elhajjajy, S. I., Elkins, K., Emili, A., Epstein, C. B., Evans, R. C., Ezkurdia, I., Fan, K., Farnham, P. J., Farrell, N. P., Feingold, E. A., Ferreira, A., Fisher-Aylor, K., Fitzgerald, S., Flicek, P., Foo, C. S., Fortier, K., Frankish, A., Freese, P., Fu, S., Fu, X., Fu, Y., Fukuda-Yuzawa, Y., Fulciniti, M., Funnell, A. P., Gabdank, I., Galeev, T., Gao, M., Giron, C. G., Garvin, T. H., Gelboin-Burkhart, C. A., Georgolopoulos, G., Gerstein, M. B., Giardine, B. M., Gifford, D. K., Gilbert, D. M., Gilchrist, D. A., Gillespie, S., Gingeras, T. R., Gong, P., Gonzalez, A., Gonzalez, J. M., Good, P., Goren, A., Gorkin, D. U., Graveley, B. R., Gray, M., Greenblatt, J. F., Griffiths, E., Groudine, M. T., Grubert, F., Gu, M., Guigo, R., Guo, H., Guo, Y., Guo, Y., Gursoy, G., Gutierrez-Arcelus, M., Halow, J., Hardison, R. C., Hardy, M., Hariharan, M., Harmanci, A., Harrington, A., Harrow, J. L., Hashimoto, T. B., Hasz, R. D., Hatan, M., Haugen, E., Hayes, J. E., He, P., He, Y., Heidari, N., Hendrickson, D., Heuston, E. F., Hilton, J. A., Hitz, B. C., Hochman, A., Holgren, C., Hou, L., Hou, S., Hsiao, Y. E., Hsu, S., Huang, H., Hubbard, T. J., Huey, J., Hughes, T. R., Hunt, T., Ibarrientos, S., Issner, R., Iwata, M., Izuogu, O., Jaakkola, T., Jameel, N., Jansen, C., Jiang, L., Jiang, P., Johnson, A., Johnson, R., Jungreis, I., Kadaba, M., Kasowski, M., Kasparian, M., Kato, M., Kaul, R., Kawli, T., Kay, M., Keen, J. C., Keles, S., Keller, C. A., Kelley, D., Kellis, M., Kheradpour, P., Kim, D. S., Kirilusha, A., Klein, R. J., Knoechel, B., Kuan, S., Kulik, M. J., Kumar, S., Kundaje, A., Kutyavin, T., Lagarde, J., Lajoie, B. R., Lambert, N. J., Lazar, J., Lee, A. Y., Lee, D., Lee, E., Lee, J. W., Lee, K., Leslie, C. S., Levy, S., Li, B., Li, H., Li, N., Li, X., Li, Y. I., Li, Y., Li, Y., Li, Y., Lian, J., Libbrecht, M. W., Lin, S., Lin, Y., Liu, D., Liu, J., Liu, P., Liu, T., Liu, X. S., Liu, Y., Liu, Y., Long, M., Lou, S., Loveland, J., Lu, A., Lu, Y., Lecuyer, E., Ma, L., Mackiewicz, M., Mannion, B. J., Mannstadt, M., Manthravadi, D., Marinov, G. K., Martin, F. J., Mattei, E., McCue, K., McEown, M., McVicker, G., Meadows, S. K., Meissner, A., Mendenhall, E. M., Messer, C. L., Meuleman, W., Meyer, C., Miller, S., Milton, M. G., Mishra, T., Moore, D. E., Moore, H. M., Moore, J. E., Moore, S. H., Moran, J., Mortazavi, A., Mudge, J. M., Munshi, N., Murad, R., Myers, R. M., Nandakumar, V., Nandi, P., Narasimha, A. M., Narayanan, A. K., Naughton, H., Navarro, F. C., Navas, P., Nazarovs, J., Nelson, J., Neph, S., Neri, F. J., Nery, J. R., Nesmith, A. R., Newberry, J. S., Newberry, K. M., Ngo, V., Nguyen, R., Nguyen, T. B., Nguyen, T., Nishida, A., Noble, W. S., Novak, C. S., Novoa, E. M., Nunez, B., O'Donnell, C. W., Olson, S., Onate, K. C., Otterman, E., Ozadam, H., Pagan, M., Palden, T., Pan, X., Park, Y., Partridge, E. C., Paten, B., Pauli-Behn, F., Pazin, M. J., Pei, B., Pennacchio, L. A., Perez, A. R., Perry, E. H., Pervouchine, D. D., Phalke, N. N., Pham, Q., Phanstiel, D. H., Plajzer-Frick, I., Pratt, G. A., Pratt, H. E., Preissl, S., Pritchard, J. K., Pritykin, Y., Purcaro, M. J., Qin, Q., Quinones-Valdez, G., Rabano, I., Radovani, E., Raj, A., Rajagopal, N., Ram, O., Ramirez, L., Ramirez, R. N., Rausch, D., Raychaudhuri, S., Raymond, J., Razavi, R., Reddy, T. E., Reimonn, T. M., Ren, B., Reymond, A., Reynolds, A., Rhie, S. K., Rinn, J., Rivera, M., Rivera-Mulia, J. C., Roberts, B. S., Rodriguez, J. M., Rozowsky, J., Ryan, R., Rynes, E., Salins, D. N., Sandstrom, R., Sasaki, T., Sathe, S., Savic, D., Scavelli, A., Scheiman, J., Schlaffner, C., Schloss, J. A., Schmitges, F. W., See, L. H., Sethi, A., Setty, M., Shafer, A., Shan, S., Sharon, E., Shen, Q., Shen, Y., Sherwood, R. I., Shi, M., Shin, S., Shoresh, N., Siebenthall, K., Sisu, C., Slifer, T., Sloan, C. A., Smith, A., Snetkova, V., Snyder, M. P., Spacek, D. V., Srinivasan, S., Srivas, R., Stamatoyannopoulos, G., Stamatoyannopoulos, J. A., Stanton, R., Steffan, D., Stehling-Sun, S., Strattan, J. S., Su, A., Sundararaman, B., Suner, M., Syed, T., Szynkarek, M., Tanaka, F. Y., Tenen, D., Teng, M., Thomas, J. A., Toffey, D., Tress, M. L., Trout, D. E., Trynka, G., Tsuji, J., Upchurch, S. A., Ursu, O., Uszczynska-Ratajczak, B., Uziel, M. C., Valencia, A., Biber, B. V., van der Velde, A. G., Van Nostrand, E. L., Vaydylevich, Y., Vazquez, J., Victorsen, A., Vielmetter, J., Vierstra, J., Visel, A., Vlasova, A., Vockley, C. M., Volpi, S., Vong, S., Wang, H., Wang, M., Wang, Q., Wang, R., Wang, T., Wang, W., Wang, X., Wang, Y., Watson, N. K., Wei, X., Wei, Z., Weisser, H., Weissman, S. M., Welch, R., Welikson, R. E., Weng, Z., Westra, H., Whitaker, J. W., White, C., White, K. P., Wildberg, A., Williams, B. A., Wine, D., Witt, H. N., Wold, B., Wolf, M., Wright, J., Xiao, R., Xiao, X., Xu, J., Xu, J., Yan, K., Yan, Y., Yang, H., Yang, X., Yang, Y., Yardimci, G. G., Yee, B. A., Yeo, G. W., Young, T., Yu, T., Yue, F., Zaleski, C., Zang, C., Zeng, H., Zeng, W., Zerbino, D. R., Zhai, J., Zhan, L., Zhan, Y., Zhang, B., Zhang, J., Zhang, J., Zhang, K., Zhang, L., Zhang, P., Zhang, Q., Zhang, X., Zhang, Y., Zhang, Z., Zhao, Y., Zheng, Y., Zhong, G., Zhou, X., Zhu, Y., Zimmerman, J., Ai, R., Li, S. 2022

  View details for DOI 10.1038/s41586-021-04226-3

  View details for PubMedID 35474001

• Early peanut introduction wins over the HLA-DQA1*01:02 allele in the interplay between environment and genetics JOURNAL OF CLINICAL INVESTIGATION Manohar, M., Nadeau, K., Kasowski, M. 2022; 132 (1)

  Abstract

  The rising incidence of food allergy in children underscores the importance of environmental exposures; however, genetic factors play a major role. How the environment and genetics interact to cause food allergy remains unclear. The landmark Learning Early About Peanut Allergy (LEAP) clinical trial established that early peanut introduction protects high-risk infants, consistent with the tolerizing effects of gut exposure. In this issue of the JCI, Kanchan et al. leveraged the LEAP trial data to examine molecular genetic mechanisms of early sensitization. A previously identified HLA risk allele for peanut allergy (DQA1*01:02) was associated with peanut-specific IgG4 levels in consumers. Notably, IgG4 antibodies likely provide protection by reducing the binding of allergen to IgE. The association of the same allele with peanut allergy in avoiders while potentially conferring protection in consumers reinforces the need to integrate genetic information toward a personalized therapeutic strategy for the best outcome in addressing food allergies.

  View details for DOI 10.1172/JCI155609

  View details for Web of Science ID 000747074000010

  View details for PubMedID 34981779

  View details for PubMedCentralID PMC8718134

• Chromatin accessibility associates with protein-RNA correlation in human cancer. Nature communications Sanghi, A., Gruber, J. J., Metwally, A., Jiang, L., Reynolds, W., Sunwoo, J., Orloff, L., Chang, H. Y., Kasowski, M., Snyder, M. P. 2021; 12 (1): 5732

  Abstract

  Although alterations in chromatin structure are known to exist in tumors, how these alterations relate to molecular phenotypes in cancer remains to be demonstrated. Multi-omics profiling of human tumors can provide insight into how alterations in chromatin structure are propagated through the pathway of gene expression to result in malignant protein expression. We applied multi-omics profiling of chromatin accessibility, RNA abundance, and protein abundance to 36 human thyroid cancer primary tumors, metastases, and patient-match normal tissue. Through quantification of chromatin accessibility associated with active transcription units and global protein expression, we identify a local chromatin structure that is highly correlated with coordinated RNA and protein expression. In particular, we identify enhancers located within gene-bodies as predictive of correlated RNA and protein expression, that is independent of overall transcriptional activity. To demonstrate the generalizability of these findings we also identify similar results in an independent cohort of human breast cancers. Taken together, these analyses suggest that local enhancers, rather than distal enhancers, are likely most predictive of cancer gene expression phenotypes. This allows for identification of potential targets for cancer therapeutic approaches and reinforces the utility of multi-omics profiling as a methodology to understand human disease.

  View details for DOI 10.1038/s41467-021-25872-1

  View details for PubMedID 34593797

• Detection of cryptogenic malignancies from metagenomic whole genome sequencing of body fluids. Genome medicine Gu, W., Talevich, E., Hsu, E., Qi, Z., Urisman, A., Federman, S., Gopez, A., Arevalo, S., Gottschall, M., Liao, L., Tung, J., Chen, L., Lim, H., Ho, C., Kasowski, M., Oak, J., Holmes, B. J., Yeh, I., Yu, J., Wang, L., Miller, S., DeRisi, J. L., Prakash, S., Simko, J., Chiu, C. Y. 2021; 13 (1): 98

  Abstract

  BACKGROUND: Metagenomic next-generation sequencing (mNGS) of body fluids is an emerging approach to identify occult pathogens in undiagnosed patients. We hypothesized that metagenomic testing can be simultaneously used to detect malignant neoplasms in addition to infectious pathogens.METHODS: From two independent studies (n = 205), we used human data generated from a metagenomic sequencing pipeline to simultaneously screen for malignancies by copy number variation (CNV) detection. In the first case-control study, we analyzed body fluid samples (n = 124) from patients with a clinical diagnosis of either malignancy (positive cases, n = 65) or infection (negative controls, n = 59). In a second verification cohort, we analyzed a series of consecutive cases (n = 81) sent to cytology for malignancy workup that included malignant positives (n = 32), negatives (n = 18), or cases with an unclear gold standard (n = 31).RESULTS: The overall CNV test sensitivity across all studies was 87% (55 of 63) in patients with malignancies confirmed by conventional cytology and/or flow cytometry testing and 68% (23 of 34) in patients who were ultimately diagnosed with cancer but negative by conventional testing. Specificity was 100% (95% CI 95-100%) with no false positives detected in 77 negative controls. In one example, a patient hospitalized with an unknown pulmonary illness had non-diagnostic lung biopsies, while CNVs implicating a malignancy were detectable from bronchoalveolar fluid.CONCLUSIONS: Metagenomic sequencing of body fluids can be used to identify undetected malignant neoplasms through copy number variation detection. This study illustrates the potential clinical utility of a single metagenomic test to uncover the cause of undiagnosed acute illnesses due to cancer or infection using the same specimen.

  View details for DOI 10.1186/s13073-021-00912-z

  View details for PubMedID 34074327

• Perspectives on ENCODE. Nature ENCODE Project Consortium, Snyder, M. P., Gingeras, T. R., Moore, J. E., Weng, Z., Gerstein, M. B., Ren, B., Hardison, R. C., Stamatoyannopoulos, J. A., Graveley, B. R., Feingold, E. A., Pazin, M. J., Pagan, M., Gilchrist, D. A., Hitz, B. C., Cherry, J. M., Bernstein, B. E., Mendenhall, E. M., Zerbino, D. R., Frankish, A., Flicek, P., Myers, R. M., Abascal, F., Acosta, R., Addleman, N. J., Adrian, J., Afzal, V., Aken, B., Akiyama, J. A., Jammal, O. A., Amrhein, H., Anderson, S. M., Andrews, G. R., Antoshechkin, I., Ardlie, K. G., Armstrong, J., Astley, M., Banerjee, B., Barkal, A. A., Barnes, I. H., Barozzi, I., Barrell, D., Barson, G., Bates, D., Baymuradov, U. K., Bazile, C., Beer, M. A., Beik, S., Bender, M. A., Bennett, R., Bouvrette, L. P., Bernstein, B. E., Berry, A., Bhaskar, A., Bignell, A., Blue, S. M., Bodine, D. M., Boix, C., Boley, N., Borrman, T., Borsari, B., Boyle, A. P., Brandsmeier, L. A., Breschi, A., Bresnick, E. H., Brooks, J. A., Buckley, M., Burge, C. B., Byron, R., Cahill, E., Cai, L., Cao, L., Carty, M., Castanon, R. G., Castillo, A., Chaib, H., Chan, E. T., Chee, D. R., Chee, S., Chen, H., Chen, H., Chen, J., Chen, S., Cherry, J. M., Chhetri, S. B., Choudhary, J. S., Chrast, J., Chung, D., Clarke, D., Cody, N. A., Coppola, C. J., Coursen, J., D'Ippolito, A. M., Dalton, S., Danyko, C., Davidson, C., Davila-Velderrain, J., Davis, C. A., Dekker, J., Deran, A., DeSalvo, G., Despacio-Reyes, G., Dewey, C. N., Dickel, D. E., Diegel, M., Diekhans, M., Dileep, V., Ding, B., Djebali, S., Dobin, A., Dominguez, D., Donaldson, S., Drenkow, J., Dreszer, T. R., Drier, Y., Duff, M. O., Dunn, D., Eastman, C., Ecker, J. R., Edwards, M. D., El-Ali, N., Elhajjajy, S. I., Elkins, K., Emili, A., Epstein, C. B., Evans, R. C., Ezkurdia, I., Fan, K., Farnham, P. J., Farrell, N., Feingold, E. A., Ferreira, A., Fisher-Aylor, K., Fitzgerald, S., Flicek, P., Foo, C. S., Fortier, K., Frankish, A., Freese, P., Fu, S., Fu, X., Fu, Y., Fukuda-Yuzawa, Y., Fulciniti, M., Funnell, A. P., Gabdank, I., Galeev, T., Gao, M., Giron, C. G., Garvin, T. H., Gelboin-Burkhart, C. A., Georgolopoulos, G., Gerstein, M. B., Giardine, B. M., Gifford, D. K., Gilbert, D. M., Gilchrist, D. A., Gillespie, S., Gingeras, T. R., Gong, P., Gonzalez, A., Gonzalez, J. M., Good, P., Goren, A., Gorkin, D. U., Graveley, B. R., Gray, M., Greenblatt, J. F., Griffiths, E., Groudine, M. T., Grubert, F., Gu, M., Guigo, R., Guo, H., Guo, Y., Guo, Y., Gursoy, G., Gutierrez-Arcelus, M., Halow, J., Hardison, R. C., Hardy, M., Hariharan, M., Harmanci, A., Harrington, A., Harrow, J. L., Hashimoto, T. B., Hasz, R. D., Hatan, M., Haugen, E., Hayes, J. E., He, P., He, Y., Heidari, N., Hendrickson, D., Heuston, E. F., Hilton, J. A., Hitz, B. C., Hochman, A., Holgren, C., Hou, L., Hou, S., Hsiao, Y. E., Hsu, S., Huang, H., Hubbard, T. J., Huey, J., Hughes, T. R., Hunt, T., Ibarrientos, S., Issner, R., Iwata, M., Izuogu, O., Jaakkola, T., Jameel, N., Jansen, C., Jiang, L., Jiang, P., Johnson, A., Johnson, R., Jungreis, I., Kadaba, M., Kasowski, M., Kasparian, M., Kato, M., Kaul, R., Kawli, T., Kay, M., Keen, J. C., Keles, S., Keller, C. A., Kelley, D., Kellis, M., Kheradpour, P., Kim, D. S., Kirilusha, A., Klein, R. J., Knoechel, B., Kuan, S., Kulik, M. J., Kumar, S., Kundaje, A., Kutyavin, T., Lagarde, J., Lajoie, B. R., Lambert, N. J., Lazar, J., Lee, A. Y., Lee, D., Lee, E., Lee, J. W., Lee, K., Leslie, C. S., Levy, S., Li, B., Li, H., Li, N., Li, X., Li, Y. I., Li, Y., Li, Y., Li, Y., Lian, J., Libbrecht, M. W., Lin, S., Lin, Y., Liu, D., Liu, J., Liu, P., Liu, T., Liu, X. S., Liu, Y., Liu, Y., Long, M., Lou, S., Loveland, J., Lu, A., Lu, Y., Lecuyer, E., Ma, L., Mackiewicz, M., Mannion, B. J., Mannstadt, M., Manthravadi, D., Marinov, G. K., Martin, F. J., Mattei, E., McCue, K., McEown, M., McVicker, G., Meadows, S. K., Meissner, A., Mendenhall, E. M., Messer, C. L., Meuleman, W., Meyer, C., Miller, S., Milton, M. G., Mishra, T., Moore, D. E., Moore, H. M., Moore, J. E., Moore, S. H., Moran, J., Mortazavi, A., Mudge, J. M., Munshi, N., Murad, R., Myers, R. M., Nandakumar, V., Nandi, P., Narasimha, A. M., Narayanan, A. K., Naughton, H., Navarro, F. C., Navas, P., Nazarovs, J., Nelson, J., Neph, S., Neri, F. J., Nery, J. R., Nesmith, A. R., Newberry, J. S., Newberry, K. M., Ngo, V., Nguyen, R., Nguyen, T. B., Nguyen, T., Nishida, A., Noble, W. S., Novak, C. S., Novoa, E. M., Nunez, B., O'Donnell, C. W., Olson, S., Onate, K. C., Otterman, E., Ozadam, H., Pagan, M., Palden, T., Pan, X., Park, Y., Partridge, E. C., Paten, B., Pauli-Behn, F., Pazin, M. J., Pei, B., Pennacchio, L. A., Perez, A. R., Perry, E. H., Pervouchine, D. D., Phalke, N. N., Pham, Q., Phanstiel, D. H., Plajzer-Frick, I., Pratt, G. A., Pratt, H. E., Preissl, S., Pritchard, J. K., Pritykin, Y., Purcaro, M. J., Qin, Q., Quinones-Valdez, G., Rabano, I., Radovani, E., Raj, A., Rajagopal, N., Ram, O., Ramirez, L., Ramirez, R. N., Rausch, D., Raychaudhuri, S., Raymond, J., Razavi, R., Reddy, T. E., Reimonn, T. M., Ren, B., Reymond, A., Reynolds, A., Rhie, S. K., Rinn, J., Rivera, M., Rivera-Mulia, J. C., Roberts, B., Rodriguez, J. M., Rozowsky, J., Ryan, R., Rynes, E., Salins, D. N., Sandstrom, R., Sasaki, T., Sathe, S., Savic, D., Scavelli, A., Scheiman, J., Schlaffner, C., Schloss, J. A., Schmitges, F. W., See, L. H., Sethi, A., Setty, M., Shafer, A., Shan, S., Sharon, E., Shen, Q., Shen, Y., Sherwood, R. I., Shi, M., Shin, S., Shoresh, N., Siebenthall, K., Sisu, C., Slifer, T., Sloan, C. A., Smith, A., Snetkova, V., Snyder, M. P., Spacek, D. V., Srinivasan, S., Srivas, R., Stamatoyannopoulos, G., Stamatoyannopoulos, J. A., Stanton, R., Steffan, D., Stehling-Sun, S., Strattan, J. S., Su, A., Sundararaman, B., Suner, M., Syed, T., Szynkarek, M., Tanaka, F. Y., Tenen, D., Teng, M., Thomas, J. A., Toffey, D., Tress, M. L., Trout, D. E., Trynka, G., Tsuji, J., Upchurch, S. A., Ursu, O., Uszczynska-Ratajczak, B., Uziel, M. C., Valencia, A., Biber, B. V., van der Velde, A. G., Van Nostrand, E. L., Vaydylevich, Y., Vazquez, J., Victorsen, A., Vielmetter, J., Vierstra, J., Visel, A., Vlasova, A., Vockley, C. M., Volpi, S., Vong, S., Wang, H., Wang, M., Wang, Q., Wang, R., Wang, T., Wang, W., Wang, X., Wang, Y., Watson, N. K., Wei, X., Wei, Z., Weisser, H., Weissman, S. M., Welch, R., Welikson, R. E., Weng, Z., Westra, H., Whitaker, J. W., White, C., White, K. P., Wildberg, A., Williams, B. A., Wine, D., Witt, H. N., Wold, B., Wolf, M., Wright, J., Xiao, R., Xiao, X., Xu, J., Xu, J., Yan, K., Yan, Y., Yang, H., Yang, X., Yang, Y., Yardimci, G. G., Yee, B. A., Yeo, G. W., Young, T., Yu, T., Yue, F., Zaleski, C., Zang, C., Zeng, H., Zeng, W., Zerbino, D. R., Zhai, J., Zhan, L., Zhan, Y., Zhang, B., Zhang, J., Zhang, J., Zhang, K., Zhang, L., Zhang, P., Zhang, Q., Zhang, X., Zhang, Y., Zhang, Z., Zhao, Y., Zheng, Y., Zhong, G., Zhou, X., Zhu, Y., Zimmerman, J. 2020; 583 (7818): 693–98

  Abstract

  The Encylopedia of DNA Elements (ENCODE) Project launched in 2003 with the long-term goal of developing a comprehensive map of functional elements in the human genome. These included genes, biochemical regions associated with gene regulation (for example, transcription factor binding sites, open chromatin, and histone marks) and transcript isoforms. The marks serve as sites for candidate cis-regulatory elements (cCREs) that may serve functional roles in regulating gene expression1. The project has been extended to model organisms, particularly the mouse. In the third phase of ENCODE, nearly a million and more than 300,000 cCRE annotations have been generated for human and mouse, respectively, and these have provided a valuable resource for the scientific community.

  View details for DOI 10.1038/s41586-020-2449-8

  View details for PubMedID 32728248

• Metabolomics in acute myeloid leukemia. Molecular genetics and metabolism Wojcicki, A. V., Kasowski, M. M., Sakamoto, K. M., Lacayo, N. 2020

  Abstract

  Acute myeloid leukemia (AML) is a complex, heterogenous hematological malignancy caused by mutations in myeloid differentiation and proliferation. Response to therapy and long-term outcomes vary widely based on chromosomal and molecular aberrations. Many platforms have been used to characterize and stratify AML. Metabolomics, the global profiling of small molecules in a biological sample, has emerged in the last decade as an important tool for studying the metabolic dependency of cancer cells. Metabolic reprogramming is not only an important manifestation of AML but clinically relevant for diagnosis, risk stratification and targeted drug development. In this review, we discuss notable metabolic studies of the last decade and their application to novel therapies.

  View details for DOI 10.1016/j.ymgme.2020.05.005

  View details for PubMedID 32457018

• Expanded encyclopaedias of DNA elements in the human and mouse genomes. Nature Moore, J. E., Purcaro, M. J., Pratt, H. E., Epstein, C. B., Shoresh, N. n., Adrian, J. n., Kawli, T. n., Davis, C. A., Dobin, A. n., Kaul, R. n., Halow, J. n., Van Nostrand, E. L., Freese, P. n., Gorkin, D. U., Shen, Y. n., He, Y. n., Mackiewicz, M. n., Pauli-Behn, F. n., Williams, B. A., Mortazavi, A. n., Keller, C. A., Zhang, X. O., Elhajjajy, S. I., Huey, J. n., Dickel, D. E., Snetkova, V. n., Wei, X. n., Wang, X. n., Rivera-Mulia, J. C., Rozowsky, J. n., Zhang, J. n., Chhetri, S. B., Zhang, J. n., Victorsen, A. n., White, K. P., Visel, A. n., Yeo, G. W., Burge, C. B., Lécuyer, E. n., Gilbert, D. M., Dekker, J. n., Rinn, J. n., Mendenhall, E. M., Ecker, J. R., Kellis, M. n., Klein, R. J., Noble, W. S., Kundaje, A. n., Guigó, R. n., Farnham, P. J., Cherry, J. M., Myers, R. M., Ren, B. n., Graveley, B. R., Gerstein, M. B., Pennacchio, L. A., Snyder, M. P., Bernstein, B. E., Wold, B. n., Hardison, R. C., Gingeras, T. R., Stamatoyannopoulos, J. A., Weng, Z. n. 2020; 583 (7818): 699–710

  Abstract

  The human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded analysis of the cell and tissue repertoires of RNA transcription, chromatin structure and modification, DNA methylation, chromatin looping, and occupancy by transcription factors and RNA-binding proteins. Here we summarize these efforts, which have produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www.encodeproject.org), including phase II ENCODE1 and Roadmap Epigenomics2 data. We have developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements, covering 7.9 and 3.4% of their respective genomes, by integrating selected datatypes associated with gene regulation, and constructed a web-based server (SCREEN; http://screen.encodeproject.org) to provide flexible, user-defined access to this resource. Collectively, the ENCODE data and registry provide an expansive resource for the scientific community to build a better understanding of the organization and function of the human and mouse genomes.

  View details for DOI 10.1038/s41586-020-2493-4

  View details for PubMedID 32728249

• Remodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension. Nature communications Reyes-Palomares, A. n., Gu, M. n., Grubert, F. n., Berest, I. n., Sa, S. n., Kasowski, M. n., Arnold, C. n., Shuai, M. n., Srivas, R. n., Miao, S. n., Li, D. n., Snyder, M. P., Rabinovitch, M. n., Zaugg, J. B. 2020; 11 (1): 1673

  Abstract

  Environmental and epigenetic factors often play an important role in polygenic disorders. However, how such factors affect disease-specific tissues at the molecular level remains to be understood. Here, we address this in pulmonary arterial hypertension (PAH). We obtain pulmonary arterial endothelial cells (PAECs) from lungs of patients and controls (n = 19), and perform chromatin, transcriptomic and interaction profiling. Overall, we observe extensive remodeling at active enhancers in PAH PAECs and identify hundreds of differentially active TFs, yet find very little transcriptomic changes in steady-state. We devise a disease-specific enhancer-gene regulatory network and predict that primed enhancers in PAH PAECs are activated by the differentially active TFs, resulting in an aberrant response to endothelial signals, which could lead to disturbed angiogenesis and endothelial-to-mesenchymal-transition. We validate these predictions for a selection of target genes in PAECs stimulated with TGF-β, VEGF or serotonin. Our study highlights the role of chromatin state and enhancers in disease-relevant cell types of PAH.

  View details for DOI 10.1038/s41467-020-15463-x

  View details for PubMedID 32245974

• Landscape of cohesin-mediated chromatin loops in the human genome. Nature Grubert, F. n., Srivas, R. n., Spacek, D. V., Kasowski, M. n., Ruiz-Velasco, M. n., Sinnott-Armstrong, N. n., Greenside, P. n., Narasimha, A. n., Liu, Q. n., Geller, B. n., Sanghi, A. n., Kulik, M. n., Sa, S. n., Rabinovitch, M. n., Kundaje, A. n., Dalton, S. n., Zaugg, J. B., Snyder, M. n. 2020; 583 (7818): 737–43

  Abstract

  Physical interactions between distal regulatory elements have a key role in regulating gene expression, but the extent to which these interactions vary between cell types and contribute to cell-type-specific gene expression remains unclear. Here, to address these questions as part of phase III of the Encyclopedia of DNA Elements (ENCODE), we mapped cohesin-mediated chromatin loops, using chromatin interaction analysis by paired-end tag sequencing (ChIA-PET), and analysed gene expression in 24 diverse human cell types, including core ENCODE cell lines. Twenty-eight per cent of all chromatin loops vary across cell types; these variations modestly correlate with changes in gene expression and are effective at grouping cell types according to their tissue of origin. The connectivity of genes corresponds to different functional classes, with housekeeping genes having few contacts, and dosage-sensitive genes being more connected to enhancer elements. This atlas of chromatin loops complements the diverse maps of regulatory architecture that comprise the ENCODE Encyclopedia, and will help to support emerging analyses of genome structure and function.

  View details for DOI 10.1038/s41586-020-2151-x

  View details for PubMedID 32728247

• An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues. Nature methods Corces, M. R., Trevino, A. E., Hamilton, E. G., Greenside, P. G., Sinnott-Armstrong, N. A., Vesuna, S. n., Satpathy, A. T., Rubin, A. J., Montine, K. S., Wu, B. n., Kathiria, A. n., Cho, S. W., Mumbach, M. R., Carter, A. C., Kasowski, M. n., Orloff, L. A., Risca, V. I., Kundaje, A. n., Khavari, P. A., Montine, T. J., Greenleaf, W. J., Chang, H. Y. 2017

  Abstract

  We present Omni-ATAC, an improved ATAC-seq protocol for chromatin accessibility profiling that works across multiple applications with substantial improvement of signal-to-background ratio and information content. The Omni-ATAC protocol generates chromatin accessibility profiles from archival frozen tissue samples and 50-μm sections, revealing the activities of disease-associated DNA elements in distinct human brain structures. The Omni-ATAC protocol enables the interrogation of personal regulomes in tissue context and translational studies.

  View details for PubMedID 28846090

• Genetic Control of Chromatin States in Humans Involves Local and Distal Chromosomal Interactions CELL Grubert, F., Zaugg, J. B., Kasowski, M., Ursu, O., Spacek, D. V., Martin, A. R., Greenside, P., Srivas, R., Phanstiel, D. H., Pekowska, A., Heidari, N., Euskirchen, G., Huber, W., Pritchard, J. K., Bustamante, C. D., Steinmetz, L. M., Kundaje, A., Snyder, M. 2015; 162 (5): 1051-1065

  Abstract

  Deciphering the impact of genetic variants on gene regulation is fundamental to understanding human disease. Although gene regulation often involves long-range interactions, it is unknown to what extent non-coding genetic variants influence distal molecular phenotypes. Here, we integrate chromatin profiling for three histone marks in lymphoblastoid cell lines (LCLs) from 75 sequenced individuals with LCL-specific Hi-C and ChIA-PET-based chromatin contact maps to uncover one of the largest collections of local and distal histone quantitative trait loci (hQTLs). Distal QTLs are enriched within topologically associated domains and exhibit largely concordant variation of chromatin state coordinated by proximal and distal non-coding genetic variants. Histone QTLs are enriched for common variants associated with autoimmune diseases and enable identification of putative target genes of disease-associated variants from genome-wide association studies. These analyses provide insights into how genetic variation can affect human disease phenotypes by coordinated changes in chromatin at interacting regulatory elements.

  View details for DOI 10.1016/j.cell.2015.07.048

  View details for Web of Science ID 000360589900015

  View details for PubMedCentralID PMC4556133

• Genetic Control of Chromatin States in Humans Involves Local and Distal Chromosomal Interactions. Cell Grubert, F., Zaugg, J. B., Kasowski, M., Ursu, O., Spacek, D. V., Martin, A. R., Greenside, P., Srivas, R., Phanstiel, D. H., Pekowska, A., Heidari, N., Euskirchen, G., Huber, W., Pritchard, J. K., Bustamante, C. D., Steinmetz, L. M., Kundaje, A., Snyder, M. 2015; 162 (5): 1051-1065

  Abstract

  Deciphering the impact of genetic variants on gene regulation is fundamental to understanding human disease. Although gene regulation often involves long-range interactions, it is unknown to what extent non-coding genetic variants influence distal molecular phenotypes. Here, we integrate chromatin profiling for three histone marks in lymphoblastoid cell lines (LCLs) from 75 sequenced individuals with LCL-specific Hi-C and ChIA-PET-based chromatin contact maps to uncover one of the largest collections of local and distal histone quantitative trait loci (hQTLs). Distal QTLs are enriched within topologically associated domains and exhibit largely concordant variation of chromatin state coordinated by proximal and distal non-coding genetic variants. Histone QTLs are enriched for common variants associated with autoimmune diseases and enable identification of putative target genes of disease-associated variants from genome-wide association studies. These analyses provide insights into how genetic variation can affect human disease phenotypes by coordinated changes in chromatin at interacting regulatory elements.

  View details for DOI 10.1016/j.cell.2015.07.048

  View details for PubMedID 26300125

• Genome-wide map of regulatory interactions in the human genome GENOME RESEARCH Heidari, N., Phanstiel, D. H., He, C., Grubert, F., Jahanbani, F., Kasowski, M., Zhang, M. Q., Snyder, M. P. 2014; 24 (12): 1905-1917

  Abstract

  Increasing evidence suggests that interactions between regulatory genomic elements play an important role in regulating gene expression. We generated a genome-wide interaction map of regulatory elements in human cells (ENCODE tier 1 cells, K562, GM12878) using Chromatin Interaction Analysis by Paired-End Tag sequencing (ChIA-PET) experiments targeting six broadly distributed factors. Bound regions covered 80% of DNase I hypersensitive sites including 99.7% of TSS and 98% of enhancers. Correlating this map with ChIP-seq and RNA-seq data sets revealed cohesin, CTCF, and ZNF143 as key components of three-dimensional chromatin structure and revealed how the distal chromatin state affects gene transcription. Comparison of interactions between cell types revealed that enhancer-promoter interactions were highly cell-type-specific. Construction and comparison of distal and proximal regulatory networks revealed stark differences in structure and biological function. Proximal binding events are enriched at genes with housekeeping functions, while distal binding events interact with genes involved in dynamic biological processes including response to stimulus. This study reveals new mechanistic and functional insights into regulatory region organization in the nucleus.

  View details for DOI 10.1101/gr.176586.114

  View details for PubMedID 25228660

• Extensive Variation in Chromatin States Across Humans SCIENCE Kasowski, M., Kyriazopoulou-Panagiotopoulou, S., Grubert, F., Zaugg, J. B., Kundaje, A., Liu, Y., Boyle, A. P., Zhang, Q. C., Zakharia, F., Spacek, D. V., Li, J., Xie, D., Olarerin-George, A., Steinmetz, L. M., Hogenesch, J. B., Kellis, M., Batzoglou, S., Snyder, M. 2013; 342 (6159): 750-752

  Abstract

  The majority of disease-associated variants lie outside protein-coding regions, suggesting a link between variation in regulatory regions and disease predisposition. We studied differences in chromatin states using five histone modifications, cohesin, and CTCF in lymphoblastoid lines from 19 individuals of diverse ancestry. We found extensive signal variation in regulatory regions, which often switch between active and repressed states across individuals. Enhancer activity is particularly diverse among individuals, whereas gene expression remains relatively stable. Chromatin variability shows genetic inheritance in trios, correlates with genetic variation and population divergence, and is associated with disruptions of transcription factor binding motifs. Overall, our results provide insights into chromatin variation among humans.

  View details for DOI 10.1126/science.1242510

  View details for PubMedID 24136358

• An integrated encyclopedia of DNA elements in the human genome NATURE Dunham, I., Kundaje, A., Aldred, S. F., Collins, P. J., Davis, C., Doyle, F., Epstein, C. B., Frietze, S., Harrow, J., Kaul, R., Khatun, J., Lajoie, B. R., Landt, S. G., Lee, B., Pauli, F., Rosenbloom, K. R., Sabo, P., Safi, A., Sanyal, A., Shoresh, N., Simon, J. M., Song, L., Trinklein, N. D., Altshuler, R. C., Birney, E., Brown, J. B., Cheng, C., Djebali, S., Dong, X., Dunham, I., Ernst, J., Furey, T. S., Gerstein, M., Giardine, B., Greven, M., Hardison, R. C., Harris, R. S., Herrero, J., Hoffman, M. M., Iyer, S., Kellis, M., Khatun, J., Kheradpour, P., Kundaje, A., Lassmann, T., Li, Q., Lin, X., Marinov, G. K., Merkel, A., Mortazavi, A., Parker, S. C., Reddy, T. E., Rozowsky, J., Schlesinger, F., Thurman, R. E., Wang, J., Ward, L. D., Whitfield, T. W., Wilder, S. P., Wu, W., Xi, H. S., Yip, K. Y., Zhuang, J., Bernstein, B. E., Birney, E., Dunham, I., Green, E. D., Gunter, C., Snyder, M., Pazin, M. J., Lowdon, R. F., Dillon, L. A., Adams, L. B., Kelly, C. J., Zhang, J., Wexler, J. R., Green, E. D., Good, P. J., Feingold, E. A., Bernstein, B. E., Birney, E., Crawford, G. E., Dekker, J., Elnitski, L., Farnham, P. J., Gerstein, M., Giddings, M. C., Gingeras, T. R., Green, E. D., Guigo, R., Hardison, R. C., Hubbard, T. J., Kellis, M., Kent, W. J., Lieb, J. D., Margulies, E. H., Myers, R. M., Snyder, M., Stamatoyannopoulos, J. A., Tenenbaum, S. A., Weng, Z., White, K. P., Wold, B., Khatun, J., Yu, Y., Wrobel, J., Risk, B. A., Gunawardena, H. P., Kuiper, H. C., Maier, C. W., Xie, L., Chen, X., Giddings, M. C., Bernstein, B. E., Epstein, C. B., Shoresh, N., Ernst, J., Kheradpour, P., Mikkelsen, T. S., Gillespie, S., Goren, A., Ram, O., Zhang, X., Wang, L., Issner, R., Coyne, M. J., Durham, T., Ku, M., Truong, T., Ward, L. D., Altshuler, R. C., Eaton, M. L., Kellis, M., Djebali, S., Davis, C. A., Merkel, A., Dobin, A., Lassmann, T., Mortazavi, A., Tanzer, A., Lagarde, J., Lin, W., Schlesinger, F., Xue, C., Marinov, G. K., Khatun, J., Williams, B. A., Zaleski, C., Rozowsky, J., Roeder, M., Kokocinski, F., Abdelhamid, R. F., Alioto, T., Antoshechkin, I., Baer, M. T., Batut, P., Bell, I., Bell, K., Chakrabortty, S., Chen, X., Chrast, J., Curado, J., Derrien, T., Drenkow, J., Dumais, E., Dumais, J., Duttagupta, R., Fastuca, M., Fejes-Toth, K., Ferreira, P., Foissac, S., Fullwood, M. J., Gao, H., Gonzalez, D., Gordon, A., Gunawardena, H. P., Howald, C., Jha, S., Johnson, R., Kapranov, P., King, B., Kingswood, C., Li, G., Luo, O. J., Park, E., Preall, J. B., Presaud, K., Ribeca, P., Risk, B. A., Robyr, D., Ruan, X., Sammeth, M., Sandhu, K. S., Schaeffer, L., See, L., Shahab, A., Skancke, J., Suzuki, A. M., Takahashi, H., Tilgner, H., Trout, D., Walters, N., Wang, H., Wrobel, J., Yu, Y., Hayashizaki, Y., Harrow, J., Gerstein, M., Hubbard, T. J., Reymond, A., Antonarakis, S. E., Hannon, G. J., Giddings, M. C., Ruan, Y., Wold, B., Carninci, P., Guigo, R., Gingeras, T. R., Rosenbloom, K. R., Sloan, C. A., Learned, K., Malladi, V. S., Wong, M. C., Barber, G., Cline, M. S., Dreszer, T. R., Heitner, S. G., Karolchik, D., Kent, W. J., Kirkup, V. M., Meyer, L. R., Long, J. C., Maddren, M., Raney, B. J., Furey, T. S., Song, L., Grasfeder, L. L., Giresi, P. G., Lee, B., Battenhouse, A., Sheffield, N. C., Simon, J. M., Showers, K. A., Safi, A., London, D., Bhinge, A. A., Shestak, C., Schaner, M. R., Kim, S. K., Zhang, Z. Z., Mieczkowski, P. A., Mieczkowska, J. O., Liu, Z., McDaniell, R. M., Ni, Y., Rashid, N. U., Kim, M. J., Adar, S., Zhang, Z., Wang, T., Winter, D., Keefe, D., Birney, E., Iyer, V. R., Lieb, J. D., Crawford, G. E., Li, G., Sandhu, K. S., Zheng, M., Wang, P., Luo, O. J., Shahab, A., Fullwood, M. J., Ruan, X., Ruan, Y., Myers, R. M., Pauli, F., Williams, B. A., Gertz, J., Marinov, G. K., Reddy, T. E., Vielmetter, J., Partridge, E. C., Trout, D., Varley, K. E., Gasper, C., Bansal, A., Pepke, S., Jain, P., Amrhein, H., Bowling, K. M., Anaya, M., Cross, M. K., King, B., Muratet, M. A., Antoshechkin, I., Newberry, K. M., McCue, K., Nesmith, A. S., Fisher-Aylor, K. I., Pusey, B., DeSalvo, G., Parker, S. L., Balasubramanian, S., Davis, N. S., Meadows, S. K., Eggleston, T., Gunter, C., Newberry, J. S., Levy, S. E., Absher, D. M., Mortazavi, A., Wong, W. H., Wold, B., Blow, M. J., Visel, A., Pennachio, L. A., Elnitski, L., Margulies, E. H., Parker, S. C., Petrykowska, H. M., Abyzov, A., Aken, B., Barrell, D., Barson, G., Berry, A., Bignell, A., Boychenko, V., Bussotti, G., Chrast, J., Davidson, C., Derrien, T., Despacio-Reyes, G., Diekhans, M., Ezkurdia, I., Frankish, A., Gilbert, J., Gonzalez, J. M., Griffiths, E., Harte, R., Hendrix, D. A., Howald, C., Hunt, T., Jungreis, I., Kay, M., Khurana, E., Kokocinski, F., Leng, J., Lin, M. F., Loveland, J., Lu, Z., Manthravadi, D., Mariotti, M., Mudge, J., Mukherjee, G., Notredame, C., Pei, B., Rodriguez, J. M., Saunders, G., Sboner, A., Searle, S., Sisu, C., Snow, C., Steward, C., Tanzer, A., Tapanari, E., Tress, M. L., van Baren, M. J., Walters, N., Washietl, S., Wilming, L., Zadissa, A., Zhang, Z., Brent, M., Haussler, D., Kellis, M., Valencia, A., Gerstein, M., Reymond, A., Guigo, R., Harrow, J., Hubbard, T. J., Landt, S. G., Frietze, S., Abyzov, A., Addleman, N., Alexander, R. P., Auerbach, R. K., Balasubramanian, S., Bettinger, K., Bhardwaj, N., Boyle, A. P., Cao, A. R., Cayting, P., Charos, A., Cheng, Y., Cheng, C., Eastman, C., Euskirchen, G., Fleming, J. D., Grubert, F., Habegger, L., Hariharan, M., Harmanci, A., Iyengar, S., Jin, V. X., Karczewski, K. J., Kasowski, M., Lacroute, P., Lam, H., Lamarre-Vincent, N., Leng, J., Lian, J., Lindahl-Allen, M., Min, R., Miotto, B., Monahan, H., Moqtaderi, Z., Mu, X. J., O'Geen, H., Ouyang, Z., Patacsil, D., Pei, B., Raha, D., Ramirez, L., Reed, B., Rozowsky, J., Sboner, A., Shi, M., Sisu, C., Slifer, T., Witt, H., Wu, L., Xu, X., Yan, K., Yang, X., Yip, K. Y., Zhang, Z., Struhl, K., Weissman, S. M., Gerstein, M., Farnham, P. J., Snyder, M., Tenenbaum, S. A., Penalva, L. O., Doyle, F., Karmakar, S., Landt, S. G., Bhanvadia, R. R., Choudhury, A., Domanus, M., Ma, L., Moran, J., Patacsil, D., Slifer, T., Victorsen, A., Yang, X., Snyder, M., White, K. P., Auer, T., Centanin, L., Eichenlaub, M., Gruhl, F., Heermann, S., Hoeckendorf, B., Inoue, D., Kellner, T., Kirchmaier, S., Mueller, C., Reinhardt, R., Schertel, L., Schneider, S., Sinn, R., Wittbrodt, B., Wittbrodt, J., Weng, Z., Whitfield, T. W., Wang, J., Collins, P. J., Aldred, S. F., Trinklein, N. D., Partridge, E. C., Myers, R. M., Dekker, J., Jain, G., Lajoie, B. R., Sanyal, A., Balasundaram, G., Bates, D. L., Byron, R., Canfield, T. K., Diegel, M. J., Dunn, D., Ebersol, A. K., Frum, T., Garg, K., Gist, E., Hansen, R. S., Boatman, L., Haugen, E., Humbert, R., Jain, G., Johnson, A. K., Johnson, E. M., Kutyavin, T. V., Lajoie, B. R., Lee, K., Lotakis, D., Maurano, M. T., Neph, S. J., Neri, F. V., Nguyen, E. D., Qu, H., Reynolds, A. P., Roach, V., Rynes, E., Sabo, P., Sanchez, M. E., Sandstrom, R. S., Sanyal, A., Shafer, A. O., Stergachis, A. B., Thomas, S., Thurman, R. E., Vernot, B., Vierstra, J., Vong, S., Wang, H., Weaver, M. A., Yan, Y., Zhang, M., Akey, J. M., Bender, M., Dorschner, M. O., Groudine, M., MacCoss, M. J., Navas, P., Stamatoyannopoulos, G., Kaul, R., Dekker, J., Stamatoyannopoulos, J. A., Dunham, I., Beal, K., Brazma, A., Flicek, P., Herrero, J., Johnson, N., Keefe, D., Lukk, M., Luscombe, N. M., Sobral, D., Vaquerizas, J. M., Wilder, S. P., Batzoglou, S., Sidow, A., Hussami, N., Kyriazopoulou-Panagiotopoulou, S., Libbrecht, M. W., Schaub, M. A., Kundaje, A., Hardison, R. C., Miller, W., Giardine, B., Harris, R. S., Wu, W., Bickel, P. J., Banfai, B., Boley, N. P., Brown, J. B., Huang, H., Li, Q., Li, J. J., Noble, W. S., Bilmes, J. A., Buske, O. J., Hoffman, M. M., Sahu, A. D., Kharchenko, P. V., Park, P. J., Baker, D., Taylor, J., Weng, Z., Iyer, S., Dong, X., Greven, M., Lin, X., Wang, J., Xi, H. S., Zhuang, J., Gerstein, M., Alexander, R. P., Balasubramanian, S., Cheng, C., Harmanci, A., Lochovsky, L., Min, R., Mu, X. J., Rozowsky, J., Yan, K., Yip, K. Y., Birney, E. 2012; 489 (7414): 57-74

  Abstract

  The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.

  View details for DOI 10.1038/nature11247

  View details for Web of Science ID 000308347000039

  View details for PubMedID 22955616

  View details for PubMedCentralID PMC3439153

• Architecture of the human regulatory network derived from ENCODE data NATURE Gerstein, M. B., Kundaje, A., Hariharan, M., Landt, S. G., Yan, K., Cheng, C., Mu, X. J., Khurana, E., Rozowsky, J., Alexander, R., Min, R., Alves, P., Abyzov, A., Addleman, N., Bhardwaj, N., Boyle, A. P., Cayting, P., Charos, A., Chen, D. Z., Cheng, Y., Clarke, D., Eastman, C., Euskirchen, G., Frietze, S., Fu, Y., Gertz, J., Grubert, F., Harmanci, A., Jain, P., Kasowski, M., Lacroute, P., Leng, J., Lian, J., Monahan, H., O'Geen, H., Ouyang, Z., Partridge, E. C., Patacsil, D., Pauli, F., Raha, D., Ramirez, L., Reddy, T. E., Reed, B., Shi, M., Slifer, T., Wang, J., Wu, L., Yang, X., Yip, K. Y., Zilberman-Schapira, G., Batzoglou, S., Sidow, A., Farnham, P. J., Myers, R. M., Weissman, S. M., Snyder, M. 2012; 489 (7414): 91-100

  Abstract

  Transcription factors bind in a combinatorial fashion to specify the on-and-off states of genes; the ensemble of these binding events forms a regulatory network, constituting the wiring diagram for a cell. To examine the principles of the human transcriptional regulatory network, we determined the genomic binding information of 119 transcription-related factors in over 450 distinct experiments. We found the combinatorial, co-association of transcription factors to be highly context specific: distinct combinations of factors bind at specific genomic locations. In particular, there are significant differences in the binding proximal and distal to genes. We organized all the transcription factor binding into a hierarchy and integrated it with other genomic information (for example, microRNA regulation), forming a dense meta-network. Factors at different levels have different properties; for instance, top-level transcription factors more strongly influence expression and middle-level ones co-regulate targets to mitigate information-flow bottlenecks. Moreover, these co-regulations give rise to many enriched network motifs (for example, noise-buffering feed-forward loops). Finally, more connected network components are under stronger selection and exhibit a greater degree of allele-specific activity (that is, differential binding to the two parental alleles). The regulatory information obtained in this study will be crucial for interpreting personal genome sequences and understanding basic principles of human biology and disease.

  View details for DOI 10.1038/nature11245

  View details for PubMedID 22955619

• Annotation of functional variation in personal genomes using RegulomeDB GENOME RESEARCH Boyle, A. P., Hong, E. L., Hariharan, M., Cheng, Y., Schaub, M. A., Kasowski, M., Karczewski, K. J., Park, J., Hitz, B. C., Weng, S., Cherry, J. M., Snyder, M. 2012; 22 (9): 1790-1797

  Abstract

  As the sequencing of healthy and disease genomes becomes more commonplace, detailed annotation provides interpretation for individual variation responsible for normal and disease phenotypes. Current approaches focus on direct changes in protein coding genes, particularly nonsynonymous mutations that directly affect the gene product. However, most individual variation occurs outside of genes and, indeed, most markers generated from genome-wide association studies (GWAS) identify variants outside of coding segments. Identification of potential regulatory changes that perturb these sites will lead to a better localization of truly functional variants and interpretation of their effects. We have developed a novel approach and database, RegulomeDB, which guides interpretation of regulatory variants in the human genome. RegulomeDB includes high-throughput, experimental data sets from ENCODE and other sources, as well as computational predictions and manual annotations to identify putative regulatory potential and identify functional variants. These data sources are combined into a powerful tool that scores variants to help separate functional variants from a large pool and provides a small set of putative sites with testable hypotheses as to their function. We demonstrate the applicability of this tool to the annotation of noncoding variants from 69 full sequenced genomes as well as that of a personal genome, where thousands of functionally associated variants were identified. Moreover, we demonstrate a GWAS where the database is able to quickly identify the known associated functional variant and provide a hypothesis as to its function. Overall, we expect this approach and resource to be valuable for the annotation of human genome sequences.

  View details for DOI 10.1101/gr.137323.112

  View details for PubMedID 22955989

• Personal Omics Profiling Reveals Dynamic Molecular and Medical Phenotypes CELL Chen, R., Mias, G. I., Li-Pook-Than, J., Jiang, L., Lam, H. Y., Chen, R., Miriami, E., Karczewski, K. J., Hariharan, M., Dewey, F. E., Cheng, Y., Clark, M. J., Im, H., Habegger, L., Balasubramanian, S., O'Huallachain, M., Dudley, J. T., Hillenmeyer, S., Haraksingh, R., Sharon, D., Euskirchen, G., Lacroute, P., Bettinger, K., Boyle, A. P., Kasowski, M., Grubert, F., Seki, S., Garcia, M., Whirl-Carrillo, M., Gallardo, M., Blasco, M. A., Greenberg, P. L., Snyder, P., Klein, T. E., Altman, R. B., Butte, A. J., Ashley, E. A., Gerstein, M., Nadeau, K. C., Tang, H., Snyder, M. 2012; 148 (6): 1293-1307

  Abstract

  Personalized medicine is expected to benefit from combining genomic information with regular monitoring of physiological states by multiple high-throughput methods. Here, we present an integrative personal omics profile (iPOP), an analysis that combines genomic, transcriptomic, proteomic, metabolomic, and autoantibody profiles from a single individual over a 14 month period. Our iPOP analysis revealed various medical risks, including type 2 diabetes. It also uncovered extensive, dynamic changes in diverse molecular components and biological pathways across healthy and diseased conditions. Extremely high-coverage genomic and transcriptomic data, which provide the basis of our iPOP, revealed extensive heteroallelic changes during healthy and diseased states and an unexpected RNA editing mechanism. This study demonstrates that longitudinal iPOP can be used to interpret healthy and diseased states by connecting genomic information with additional dynamic omics activity.

  View details for DOI 10.1016/j.cell.2012.02.009

  View details for PubMedID 22424236

• A User's Guide to the Encyclopedia of DNA Elements (ENCODE) PLOS BIOLOGY Myers, R. M., Stamatoyannopoulos, J., Snyder, M., Dunham, I., Hardison, R. C., Bernstein, B. E., Gingeras, T. R., Kent, W. J., Birney, E., Wold, B., Crawford, G. E., Bernstein, B. E., Epstein, C. B., Shoresh, N., Ernst, J., Mikkelsen, T. S., Kheradpour, P., Zhang, X., Wang, L., Issner, R., Coyne, M. J., Durham, T., Ku, M., Thanh Truong, T., Ward, L. D., Altshuler, R. C., Lin, M. F., Kellis, M., Gingeras, T. R., Davis, C. A., Kapranov, P., Dobin, A., Zaleski, C., Schlesinger, F., Batut, P., Chakrabortty, S., Jha, S., Lin, W., Drenkow, J., Wang, H., Bell, K., Gao, H., Bell, I., Dumais, E., Dumais, J., Antonarakis, S. E., Ucla, C., Borel, C., Guigo, R., Djebali, S., Lagarde, J., Kingswood, C., Ribeca, P., Sammeth, M., Alioto, T., Merkel, A., Tilgner, H., Carninci, P., Hayashizaki, Y., Lassmann, T., Takahashi, H., Abdelhamid, R. F., Hannon, G., Fejes-Toth, K., Preall, J., Gordon, A., Sotirova, V., Reymond, A., Howald, C., Graison, E. A., Chrast, J., Ruan, Y., Ruan, X., Shahab, A., Poh, W. T., Wei, C., Crawford, G. E., Furey, T. S., Boyle, A. P., Sheffield, N. C., Song, L., Shibata, Y., Vales, T., Winter, D., Zhang, Z., London, D., Wang, T., Birney, E., Keefe, D., Iyer, V. R., Lee, B., McDaniell, R. M., Liu, Z., Battenhouse, A., Bhinge, A. A., Lieb, J. D., Grasfeder, L. L., Showers, K. A., Giresi, P. G., Kim, S. K., Shestak, C., Myers, R. M., Pauli, F., Reddy, T. E., Gertz, J., Partridge, E. C., Jain, P., Sprouse, R. O., Bansal, A., Pusey, B., Muratet, M. A., Varley, K. E., Bowling, K. M., Newberry, K. M., Nesmith, A. S., Dilocker, J. A., Parker, S. L., Waite, L. L., Thibeault, K., Roberts, K., Absher, D. M., Wold, B., Mortazavi, A., Williams, B., Marinov, G., Trout, D., Pepke, S., King, B., McCue, K., Kirilusha, A., DeSalvo, G., Fisher-Aylor, K., Amrhein, H., Vielmetter, J., Sherlock, G., Sidow, A., Batzoglou, S., Rauch, R., Kundaje, A., Libbrecht, M., Margulies, E. H., Parker, S. C., Elnitski, L., Green, E. D., Hubbard, T., Harrow, J., Searle, S., Kokocinski, F., Aken, B., Frankish, A., Hunt, T., Despacio-Reyes, G., Kay, M., Mukherjee, G., Bignell, A., Saunders, G., Boychenko, V., Brent, M., van Baren, M. J., Brown, R. H., Gerstein, M., Khurana, E., Balasubramanian, S., Zhang, Z., Lam, H., Cayting, P., Robilotto, R., Lu, Z., Guigo, R., Derrien, T., Tanzer, A., Knowles, D. G., Mariotti, M., Kent, W. J., Haussler, D., Harte, R., Diekhans, M., Kellis, M., Lin, M., Kheradpour, P., Ernst, J., Reymond, A., Howald, C., Graison, E. A., Chrast, J., Valencia, A., Tress, M., Manuel Rodriguez, J., Snyder, M., Landt, S. G., Raha, D., Shi, M., Euskirchen, G., Grubert, F., Kasowski, M., Lian, J., Cayting, P., Lacroute, P., Xu, Y., Monahan, H., Patacsil, D., Slifer, T., Yang, X., Charos, A., Reed, B., Wu, L., Auerbach, R. K., Habegger, L., Hariharan, M., Rozowsky, J., Abyzov, A., Weissman, S. M., Gerstein, M., Struhl, K., Lamarre-Vincent, N., Lindahl-Allen, M., Miotto, B., Moqtaderi, Z., Fleming, J. D., Newburger, P., Farnham, P. J., Frietze, S., O'Geen, H., Xu, X., Blahnik, K. R., Cao, A. R., Iyengar, S., Stamatoyannopoulos, J. A., Kaul, R., Thurman, R. E., Wang, H., Navas, P. A., Sandstrom, R., Sabo, P. J., Weaver, M., Canfield, T., Lee, K., Neph, S., Roach, V., Reynolds, A., Johnson, A., Rynes, E., Giste, E., Vong, S., Neri, J., Frum, T., Johnson, E. M., Nguyen, E. D., Ebersol, A. K., Sanchez, M. E., Sheffer, H. H., Lotakis, D., Haugen, E., Humbert, R., Kutyavin, T., Shafer, T., Dekker, J., Lajoie, B. R., Sanyal, A., Kent, W. J., Rosenbloom, K. R., Dreszer, T. R., Raney, B. J., Barber, G. P., Meyer, L. R., Sloan, C. A., Malladi, V. S., Cline, M. S., Learned, K., Swing, V. K., Zweig, A. S., Rhead, B., Fujita, P. A., Roskin, K., Karolchik, D., Kuhn, R. M., Haussler, D., Birney, E., Dunham, I., Wilder, S. P., Keefe, D., Sobral, D., Herrero, J., Beal, K., Lukk, M., Brazma, A., Vaquerizas, J. M., Luscombe, N. M., Bickel, P. J., Boley, N., Brown, J. B., Li, Q., Huang, H., Gerstein, M., Habegger, L., Sboner, A., Rozowsky, J., Auerbach, R. K., Yip, K. Y., Cheng, C., Yan, K., Bhardwaj, N., Wang, J., Lochovsky, L., Jee, J., Gibson, T., Leng, J., Du, J., Hardison, R. C., Harris, R. S., Song, G., Miller, W., Haussler, D., Roskin, K., Suh, B., Wang, T., Paten, B., Noble, W. S., Hoffman, M. M., Buske, O. J., Weng, Z., Dong, X., Wang, J., Xi, H., Tenenbaum, S. A., Doyle, F., Penalva, L. O., Chittur, S., Tullius, T. D., Parker, S. C., White, K. P., Karmakar, S., Victorsen, A., Jameel, N., Bild, N., Grossman, R. L., Snyder, M., Landt, S. G., Yang, X., Patacsil, D., Slifer, T., Dekker, J., Lajoie, B. R., Sanyal, A., Weng, Z., Whitfield, T. W., Wang, J., Collins, P. J., Trinklein, N. D., Partridge, E. C., Myers, R. M., Giddings, M. C., Chen, X., Khatun, J., Maier, C., Yu, Y., Gunawardena, H., Risk, B., Feingold, E. A., Lowdon, R. F., Dillon, L. A., Good, P. J. 2011; 9 (4)

  Abstract

  The mission of the Encyclopedia of DNA Elements (ENCODE) Project is to enable the scientific and medical communities to interpret the human genome sequence and apply it to understand human biology and improve health. The ENCODE Consortium is integrating multiple technologies and approaches in a collective effort to discover and define the functional elements encoded in the human genome, including genes, transcripts, and transcriptional regulatory regions, together with their attendant chromatin states and DNA methylation patterns. In the process, standards to ensure high-quality data have been implemented, and novel algorithms have been developed to facilitate analysis. Data and derived results are made available through a freely accessible database. Here we provide an overview of the project and the resources it is generating and illustrate the application of ENCODE data to interpret the human genome.

  View details for DOI 10.1371/journal.pbio.1001046

  View details for Web of Science ID 000289938900014

• Variation in Transcription Factor Binding Among Humans SCIENCE Kasowski, M., Grubert, F., Heffelfinger, C., Hariharan, M., Asabere, A., Waszak, S. M., Habegger, L., Rozowsky, J., Shi, M., Urban, A. E., Hong, M., Karczewski, K. J., Huber, W., Weissman, S. M., Gerstein, M. B., Korbel, J. O., Snyder, M. 2010; 328 (5975): 232-235

  Abstract

  Differences in gene expression may play a major role in speciation and phenotypic diversity. We examined genome-wide differences in transcription factor (TF) binding in several humans and a single chimpanzee by using chromatin immunoprecipitation followed by sequencing. The binding sites of RNA polymerase II (PolII) and a key regulator of immune responses, nuclear factor kappaB (p65), were mapped in 10 lymphoblastoid cell lines, and 25 and 7.5% of the respective binding regions were found to differ between individuals. Binding differences were frequently associated with single-nucleotide polymorphisms and genomic structural variants, and these differences were often correlated with differences in gene expression, suggesting functional consequences of binding variation. Furthermore, comparing PolII binding between humans and chimpanzee suggests extensive divergence in TF binding. Our results indicate that many differences in individuals and species occur at the level of TF binding, and they provide insight into the genetic events responsible for these differences.

  View details for DOI 10.1126/science.1183621

  View details for Web of Science ID 000276459600043

  View details for PubMedID 20299548

  View details for PubMedCentralID PMC2938768