Emma Monte

All Publications

• Single-cell spatial mapping reveals alteration of cell type composition and tissue microenvironment during early colorectal cancer formation. bioRxiv : the preprint server for biology Guha, T. K., Esplin, E. D., Horning, A. M., Chiu, R., Paul, K., Weimer, A. K., Becker, W. R., Laquindanum, R., Mills, M. A., Glen Esplin, D., Shen, J., Monte, E., White, S., Karathanos, T. V., Cotter, D., Bi, J., Ladabaum, U., Longacre, T. A., Curtis, C., Greenleaf, W. J., Ford, J. M., Snyder, M. P. 2024

  Abstract

  Colorectal cancer (CRC) is the third leading cause of cancer mortality in the United States. Familial adenomatous polyposis (FAP) is a hereditary syndrome that raises the risk of developing CRC, with total colectomy as the only effective prevention. Even though FAP is rare (0.5% of all CRC cases), this disease model is well suited for studying the early stages of malignant transformation as patients form many polyps reflective of pre-cancer states. In order to spatially profile and analyze the pre-cancer and tumor microenvironment, we have performed single-cell multiplexed imaging for 52 samples: 12 normal mucosa,16 FAP mucosa,18 FAP polyps, 2 FAP adenocarcinoma, and 4 sporadic colorectal cancer (CRCs) using Co-detection by Indexing (CODEX) imaging platform. The data revealed significant changes in cell type composition occurring in early stage polyps and during the malignant transformation of polyps to CRC. We observe a decrease in CD4+/CD8+ T cell ratio and M1/M2 macrophage ratio along the FAP disease continuum. Advanced dysplastic polyps show a higher population of cancer associated fibroblasts (CAFs), which likely alter the pre-cancer microenvironment. Within polyps and CRCs, we observe strong nuclear expression of beta-catenin and higher number neo-angiogenesis events, unlike FAP mucosa and normal colon counterparts. We identify an increase in cancer stem cells (CSCs) within the glandular crypts of the FAP polyps and also detect Tregs, tumor associated macrophages (TAMs) and vascular endothelial cells supporting CSC survival and proliferation. We detect a potential immunosuppressive microenvironment within the tumor 'nest' of FAP adenocarcinoma samples, where tumor cells tend to segregate and remain distant from the invading immune cells. TAMs were found to infiltrate the tumor area, along with angiogenesis and tumor proliferation. CAFs were found to be enriched near the inflammatory region within polyps and CRCs and may have several roles in supporting tumor growth. Neighborhood analyses between adjacent FAP mucosa and FAP polyps show significant differences in spatial location of cells based on functionality. For example, in FAP mucosa, naive CD4+ T cells alone tend to localize near the fibroblast within the stromal compartment. However, in FAP polyp, CD4+T cells colocalize with the macrophages for T cell activation. Our data are expected to serve as a useful resource for understanding the early stages of neogenesis and the pre-cancer microenvironment, which may benefit early detection, therapeutic intervention and future prevention.

  View details for DOI 10.1101/2024.11.20.622725

  View details for PubMedID 39605357

• Multiomic analysis of familial adenomatous polyposis reveals molecular pathways associated with early tumorigenesis. Nature cancer Esplin, E. D., Hanson, C., Wu, S., Horning, A. M., Barapour, N., Nevins, S. A., Jiang, L., Contrepois, K., Lee, H., Guha, T. K., Hu, Z., Laquindanum, R., Mills, M. A., Chaib, H., Chiu, R., Jian, R., Chan, J., Ellenberger, M., Becker, W. R., Bahmani, B., Khan, A., Michael, B., Weimer, A. K., Esplin, D. G., Shen, J., Lancaster, S., Monte, E., Karathanos, T. V., Ladabaum, U., Longacre, T. A., Kundaje, A., Curtis, C., Greenleaf, W. J., Ford, J. M., Snyder, M. P. 2024

  Abstract

  Familial adenomatous polyposis (FAP) is a genetic disease causing hundreds of premalignant polyps in affected persons and is an ideal model to study transitions of early precancer states to colorectal cancer (CRC). We performed deep multiomic profiling of 93 samples, including normal mucosa, benign polyps and dysplastic polyps, from six persons with FAP. Transcriptomic, proteomic, metabolomic and lipidomic analyses revealed a dynamic choreography of thousands of molecular and cellular events that occur during precancerous transitions toward cancer formation. These involve processes such as cell proliferation, immune response, metabolic alterations (including amino acids and lipids), hormones and extracellular matrix proteins. Interestingly, activation of the arachidonic acid pathway was found to occur early in hyperplasia; this pathway is targeted by aspirin and other nonsteroidal anti-inflammatory drugs, a preventative treatment under investigation in persons with FAP. Overall, our results reveal key genomic, cellular and molecular events during the earliest steps in CRC formation and potential mechanisms of pharmaceutical prophylaxis.

  View details for DOI 10.1038/s43018-024-00831-z

  View details for PubMedID 39478120

  View details for PubMedCentralID 2706149

• Global loss of promoter-enhancer connectivity and rebalancing of gene expression during early colorectal cancer carcinogenesis. Nature cancer Zhu, Y., Lee, H., White, S., Weimer, A. K., Monte, E., Horning, A., Nevins, S. A., Esplin, E. D., Paul, K., Krieger, G., Shipony, Z., Chiu, R., Laquindanum, R., Karathanos, T. V., Chua, M. W., Mills, M., Ladabaum, U., Longacre, T., Shen, J., Jaimovich, A., Lipson, D., Kundaje, A., Greenleaf, W. J., Curtis, C., Ford, J. M., Snyder, M. P. 2024

  Abstract

  Although three-dimensional (3D) genome architecture is crucial for gene regulation, its role in disease remains elusive. We traced the evolution and malignant transformation of colorectal cancer (CRC) by generating high-resolution chromatin conformation maps of 33 colon samples spanning different stages of early neoplastic growth in persons with familial adenomatous polyposis (FAP). Our analysis revealed a substantial progressive loss of genome-wide cis-regulatory connectivity at early malignancy stages, correlating with nonlinear gene regulation effects. Genes with high promoter-enhancer (P-E) connectivity in unaffected mucosa were not linked to elevated baseline expression but tended to be upregulated in advanced stages. Inhibiting highly connected promoters preferentially represses gene expression in CRC cells compared to normal colonic epithelial cells. Our results suggest a two-phase model whereby neoplastic transformation reduces P-E connectivity from a redundant state to a rate-limiting one for transcriptional levels, highlighting the intricate interplay between 3D genome architecture and gene regulation during early CRC progression.

  View details for DOI 10.1038/s43018-024-00823-z

  View details for PubMedID 39478119

  View details for PubMedCentralID 7541718

• LONG-READ RNA ISOFORM MAP OF THE HUMAN BRAIN (ISOHUB) Lin, X., Hadas, Y., Hadjimichael, E., Li, L., Monte, E., Koornstra, E., Shieh, A., van Bakel, H., Snyder, M., Hallmayer, J., Wang, X., Liu, C., Urban, A., Pinto, D., PsychENCODE Consortium ELSEVIER. 2024: 86

  View details for DOI 10.1016/j.euroneuro.2024.08.181

  View details for Web of Science ID 001336799000152

• Deconvolution of polygenic risk score in single cells unravels cellular and molecular heterogeneity of complex human diseases. bioRxiv : the preprint server for biology Zhang, S., Shu, H., Zhou, J., Rubin-Sigler, J., Yang, X., Liu, Y., Cooper-Knock, J., Monte, E., Zhu, C., Tu, S., Li, H., Tong, M., Ecker, J. R., Ichida, J. K., Shen, Y., Zeng, J., Tsao, P. S., Snyder, M. P. 2024

  Abstract

  Polygenic risk scores (PRSs) are commonly used for predicting an individual's genetic risk of complex diseases. Yet, their implication for disease pathogenesis remains largely limited. Here, we introduce scPRS, a geometric deep learning model that constructs single-cell-resolved PRS leveraging reference single-cell chromatin accessibility profiling data to enhance biological discovery as well as disease prediction. Real-world applications across multiple complex diseases, including type 2 diabetes (T2D), hypertrophic cardiomyopathy (HCM), and Alzheimer's disease (AD), showcase the superior prediction power of scPRS compared to traditional PRS methods. Importantly, scPRS not only predicts disease risk but also uncovers disease-relevant cells, such as hormone-high alpha and beta cells for T2D, cardiomyocytes and pericytes for HCM, and astrocytes, microglia and oligodendrocyte progenitor cells for AD. Facilitated by a layered multi-omic analysis, scPRS further identifies cell-type-specific genetic underpinnings, linking disease-associated genetic variants to gene regulation within corresponding cell types. We substantiate the disease relevance of scPRS-prioritized HCM genes and demonstrate that the suppression of these genes in HCM cardiomyocytes is rescued by Mavacamten treatment. Additionally, we establish a novel microglia-specific regulatory relationship between the AD risk variant rs7922621 and its target genes ANXA11 and TSPAN14. We further illustrate the detrimental effects of suppressing these two genes on microglia phagocytosis. Our work provides a multi-tasking, interpretable framework for precise disease prediction and systematic investigation of the genetic, cellular, and molecular basis of complex diseases, laying the methodological foundation for single-cell genetics.

  View details for DOI 10.1101/2024.05.14.594252

  View details for PubMedID 38798507

  View details for PubMedCentralID PMC11118500

• Personalized transcriptome signatures in a cardiomyopathy stem cell biobank. bioRxiv : the preprint server for biology Monte, E., Furihata, T., Wang, G., Perea-Gil, I., Wei, E., Chaib, H., Nair, R., Guevara, J. V., Mares, R., Cheng, X., Zhuge, Y., Black, K., Serrano, R., Dagan-Rosenfeld, O., Maguire, P., Mercola, M., Karakikes, I., Wu, J. C., Snyder, M. P. 2024

  Abstract

  There is growing evidence that pathogenic mutations do not fully explain hypertrophic (HCM) or dilated (DCM) cardiomyopathy phenotypes. We hypothesized that if a patient's genetic background was influencing cardiomyopathy this should be detectable as signatures in gene expression. We built a cardiomyopathy biobank resource for interrogating personalized genotype phenotype relationships in human cell lines.We recruited 308 diseased and control patients for our cardiomyopathy stem cell biobank. We successfully reprogrammed PBMCs (peripheral blood mononuclear cells) into induced pluripotent stem cells (iPSCs) for 300 donors. These iPSCs underwent whole genome sequencing and were differentiated into cardiomyocytes for RNA-seq. In addition to annotating pathogenic variants, mutation burden in a panel of cardiomyopathy genes was assessed for correlation with echocardiogram measurements. Line-specific co-expression networks were inferred to evaluate transcriptomic subtypes. Drug treatment targeted the sarcomere, either by activation with omecamtiv mecarbil or inhibition with mavacamten, to alter contractility.We generated an iPSC biobank from 300 donors, which included 101 individuals with HCM and 88 with DCM. Whole genome sequencing of 299 iPSC lines identified 78 unique pathogenic or likely pathogenic mutations in the diseased lines. Notably, only DCM lines lacking a known pathogenic or likely pathogenic mutation replicated a finding in the literature for greater nonsynonymous SNV mutation burden in 102 cardiomyopathy genes to correlate with lower left ventricular ejection fraction in DCM. We analyzed RNA-sequencing data from iPSC-derived cardiomyocytes for 102 donors. Inferred personalized co-expression networks revealed two transcriptional subtypes of HCM. The first subtype exhibited concerted activation of the co-expression network, with the degree of activation reflective of the disease severity of the donor. In contrast, the second HCM subtype and the entire DCM cohort exhibited partial activation of the respective disease network, with the strength of specific gene by gene relationships dependent on the iPSC-derived cardiomyocyte line. ADCY5 was the largest hubnode in both the HCM and DCM networks and partially corrected in response to drug treatment.We have a established a stem cell biobank for studying cardiomyopathy. Our analysis supports the hypothesis the genetic background influences pathologic gene expression programs and support a role for ADCY5 in cardiomyopathy.

  View details for DOI 10.1101/2024.05.10.593618

  View details for PubMedID 38798547

  View details for PubMedCentralID PMC11118309

• Author Correction: Advances and prospects for the Human BioMolecular Atlas Program (HuBMAP). Nature cell biology Jain, S., Pei, L., Spraggins, J. M., Angelo, M., Carson, J. P., Gehlenborg, N., Ginty, F., Goncalves, J. P., Hagood, J. S., Hickey, J. W., Kelleher, N. L., Laurent, L. C., Lin, S., Lin, Y., Liu, H., Naba, A., Nakayasu, E. S., Qian, W., Radtke, A., Robson, P., Stockwell, B. R., Van de Plas, R., Vlachos, I. S., Zhou, M., HuBMAP Consortium, Borner, K., Snyder, M. P., Ahn, K. J., Allen, J., Anderson, D. M., Anderton, C. R., Curcio, C., Angelin, A., Arvanitis, C., Atta, L., Awosika-Olumo, D., Bahmani, A., Bai, H., Balderrama, K., Balzano, L., Bandyopadhyay, G., Bandyopadhyay, S., Bar-Joseph, Z., Barnhart, K., Barwinska, D., Becich, M., Becker, L., Becker, W., Bedi, K., Bendall, S., Benninger, K., Betancur, D., Bettinger, K., Billings, S., Blood, P., Bolin, D., Border, S., Bosse, M., Bramer, L., Brewer, M., Brusko, M., Bueckle, A., Burke, K., Burnum-Johnson, K., Butcher, E., Butterworth, E., Cai, L., Calandrelli, R., Caldwell, M., Campbell-Thompson, M., Cao, D., Cao-Berg, I., Caprioli, R., Caraccio, C., Caron, A., Carroll, M., Chadwick, C., Chen, A., Chen, D., Chen, F., Chen, H., Chen, J., Chen, L., Chen, L., Chiacchia, K., Cho, S., Chou, P., Choy, L., Cisar, C., Clair, G., Clarke, L., Clouthier, K. A., Colley, M. E., Conlon, K., Conroy, J., Contrepois, K., Corbett, A., Corwin, A., Cotter, D., Courtois, E., Cruz, A., Csonka, C., Czupil, K., Daiya, V., Dale, K., Davanagere, S. A., Dayao, M., de Caestecker, M. P., Decker, A., Deems, S., Degnan, D., Desai, T., Deshpande, V., Deutsch, G., Devlin, M., Diep, D., Dodd, C., Donahue, S., Dong, W., Dos Santos Peixoto, R., Duffy, M., Dufresne, M., Duong, T. E., Dutra, J., Eadon, M. T., El-Achkar, T. M., Enninful, A., Eraslan, G., Eshelman, D., Espin-Perez, A., Esplin, E. D., Esselman, A., Falo, L. D., Falo, L., Fan, J., Fan, R., Farrow, M. A., Farzad, N., Favaro, P., Fermin, J., Filiz, F., Filus, S., Fisch, K., Fisher, E., Fisher, S., Flowers, K., Flynn, W. F., Fogo, A. B., Fu, D. A., Fulcher, J., Fung, A., Furst, D., Gallant, M., Gao, F., Gao, Y., Gaulton, K., Gaut, J. P., Gee, J., Ghag, R. R., Ghazanfar, S., Ghose, S., Gisch, D., Gold, I., Gondalia, A., Gorman, B., Greenleaf, W., Greenwald, N., Gregory, B., Guo, R., Gupta, R., Hakimian, H., Haltom, J., Halushka, M., Han, K. S., Hanson, C., Harbury, P., Hardi, J., Harlan, L., Harris, R. C., Hartman, A., Heidari, E., Helfer, J., Helminiak, D., Hemberg, M., Henning, N., Herr, B. W., Ho, J., Holden-Wiltse, J., Hong, S., Hong, Y., Honick, B., Hood, G., Hu, P., Hu, Q., Huang, M., Huyck, H., Imtiaz, T., Isberg, O. G., Itkin, M., Jackson, D., Jacobs, M., Jain, Y., Jewell, D., Jiang, L., Jiang, Z. G., Johnston, S., Joshi, P., Ju, Y., Judd, A., Kagel, A., Kahn, A., Kalavros, N., Kalhor, K., Karagkouni, D., Karathanos, T., Karunamurthy, A., Katari, S., Kates, H., Kaushal, M., Keener, N., Keller, M., Kenney, M., Kern, C., Kharchenko, P., Kim, J., Kingsford, C., Kirwan, J., Kiselev, V., Kishi, J., Kitata, R. B., Knoten, A., Kollar, C., Krishnamoorthy, P., Kruse, A. R., Da, K., Kundaje, A., Kutschera, E., Kwon, Y., Lake, B. B., Lancaster, S., Langlieb, J., Lardenoije, R., Laronda, M., Laskin, J., Lau, K., Lee, H., Lee, M., Lee, M., Strekalova, Y. L., Li, D., Li, J., Li, J., Li, X., Li, Z., Liao, Y., Liaw, T., Lin, P., Lin, Y., Lindsay, S., Liu, C., Liu, Y., Liu, Y., Lott, M., Lotz, M., Lowery, L., Lu, P., Lu, X., Lucarelli, N., Lun, X., Luo, Z., Ma, J., Macosko, E., Mahajan, M., Maier, L., Makowski, D., Malek, M., Manthey, D., Manz, T., Margulies, K., Marioni, J., Martindale, M., Mason, C., Mathews, C., Maye, P., McCallum, C., McDonough, E., McDonough, L., Mcdowell, H., Meads, M., Medina-Serpas, M., Ferreira, R. M., Messinger, J., Metis, K., Migas, L. G., Miller, B., Mimar, S., Minor, B., Misra, R., Missarova, A., Mistretta, C., Moens, R., Moerth, E., Moffitt, J., Molla, G., Monroe, M., Monte, E., Morgan, M., Muraro, D., Murphy, B. R., Murray, E., Musen, M. A., Naglah, A., Nasamran, C., Neelakantan, T., Nevins, S., Nguyen, H., Nguyen, N., Nguyen, T., Nguyen, T., Nigra, D., Nofal, M., Nolan, G., Nwanne, G., O'Connor, M., Okuda, K., Olmer, M., O'Neill, K., Otaluka, N., Pang, M., Parast, M., Pasa-Tolic, L., Paten, B., Patterson, N. H., Peng, T., Phillips, G., Pichavant, M., Piehowski, P., Pilner, H., Pingry, E., Pita-Juarez, Y., Plevritis, S., Ploumakis, A., Pouch, A., Pryhuber, G., Puerto, J., Qaurooni, D., Qin, L., Quardokus, E. M., Rajbhandari, P., Rakow-Penner, R., Ramasamy, R., Read, D., Record, E. G., Reeves, D., Ricarte, A., Rodriguez-Soto, A., Ropelewski, A., Rosario, J., Roselkis, M., Rowe, D., Roy, T. K., Ruffalo, M., Ruschman, N., Sabo, A., Sachdev, N., Saka, S., Salamon, D., Sarder, P., Sasaki, H., Satija, R., Saunders, D., Sawka, R., Schey, K., Schlehlein, H., Scholten, D., Schultz, S., Schwartz, L., Schwenk, M., Scibek, R., Segre, A., Serrata, M., Shands, W., Shen, X., Shendure, J., Shephard, H., Shi, L., Shi, T., Shin, D., Shirey, B., Sibilla, M., Silber, M., Silverstein, J., Simmel, D., Simmons, A., Singhal, D., Sivajothi, S., Smits, T., Soncin, F., Song, Q., Stanley, V., Stuart, T., Su, H., Su, P., Sun, X., Surrette, C., Swahn, H., Tan, K., Teichmann, S., Tejomay, A., Tellides, G., Thomas, K., Thomas, T., Thompson, M., Tian, H., Tideman, L., Trapnell, C., Tsai, A. G., Tsai, C., Tsai, L., Tsui, E., Tsui, T., Tung, J., Turner, M., Uranic, J., Vaishnav, E. D., Varra, S. R., Vaskivskyi, V., Velickovic, D., Velickovic, M., Verheyden, J., Waldrip, J., Wallace, D., Wan, X., Wang, A., Wang, F., Wang, M., Wang, S., Wang, X., Wasserfall, C., Wayne, L., Webber, J., Weber, G. M., Wei, B., Wei, J., Weimer, A., Welling, J., Wen, X., Wen, Z., Williams, M., Winfree, S., Winograd, N., Woodard, A., Wright, D., Wu, F., Wu, P., Wu, Q., Wu, X., Xing, Y., Xu, T., Yang, M., Yang, M., Yap, J., Ye, D. H., Yin, P., Yuan, Z., Yun, C. J., Zahraei, A., Zemaitis, K., Zhang, B., Zhang, C., Zhang, C., Zhang, C., Zhang, K., Zhang, S., Zhang, T., Zhang, Y., Zhao, B., Zhao, W., Zheng, J. W., Zhong, S., Zhu, B., Zhu, C., Zhu, D., Zhu, Q., Zhu, Y. 2024

  View details for DOI 10.1038/s41556-024-01384-0

  View details for PubMedID 38429479

• Detection and analysis of complex structural variation in human genomes across populations and in brains of donors with psychiatric disorders Cell Zhou, B., Arthur, J. G., Guo, H., et al 2024; Published online September 30, 2024

  View details for DOI 10.1016/j.cell.2024.09.014

• Advances and prospects for the Human BioMolecular Atlas Program (HuBMAP). Nature cell biology Jain, S., Pei, L., Spraggins, J. M., Angelo, M., Carson, J. P., Gehlenborg, N., Ginty, F., Gonçalves, J. P., Hagood, J. S., Hickey, J. W., Kelleher, N. L., Laurent, L. C., Lin, S., Lin, Y., Liu, H., Naba, A., Nakayasu, E. S., Qian, W. J., Radtke, A., Robson, P., Stockwell, B. R., Van de Plas, R., Vlachos, I. S., Zhou, M., Börner, K., Snyder, M. P. 2023

  Abstract

  The Human BioMolecular Atlas Program (HuBMAP) aims to create a multi-scale spatial atlas of the healthy human body at single-cell resolution by applying advanced technologies and disseminating resources to the community. As the HuBMAP moves past its first phase, creating ontologies, protocols and pipelines, this Perspective introduces the production phase: the generation of reference spatial maps of functional tissue units across many organs from diverse populations and the creation of mapping tools and infrastructure to advance biomedical research.

  View details for DOI 10.1038/s41556-023-01194-w

  View details for PubMedID 37468756

  View details for PubMedCentralID 8238499

• Organization of the human intestine at single-cell resolution. Nature Hickey, J. W., Becker, W. R., Nevins, S. A., Horning, A., Perez, A. E., Zhu, C., Zhu, B., Wei, B., Chiu, R., Chen, D. C., Cotter, D. L., Esplin, E. D., Weimer, A. K., Caraccio, C., Venkataraaman, V., Schürch, C. M., Black, S., Brbić, M., Cao, K., Chen, S., Zhang, W., Monte, E., Zhang, N. R., Ma, Z., Leskovec, J., Zhang, Z., Lin, S., Longacre, T., Plevritis, S. K., Lin, Y., Nolan, G. P., Greenleaf, W. J., Snyder, M. 2023; 619 (7970): 572-584

  Abstract

  The intestine is a complex organ that promotes digestion, extracts nutrients, participates in immune surveillance, maintains critical symbiotic relationships with microbiota and affects overall health1. The intesting has a length of over nine metres, along which there are differences in structure and function2. The localization of individual cell types, cell type development trajectories and detailed cell transcriptional programs probably drive these differences in function. Here, to better understand these differences, we evaluated the organization of single cells using multiplexed imaging and single-nucleus RNA and open chromatin assays across eight different intestinal sites from nine donors. Through systematic analyses, we find cell compositions that differ substantially across regions of the intestine and demonstrate the complexity of epithelial subtypes, and find that the same cell types are organized into distinct neighbourhoods and communities, highlighting distinct immunological niches that are present in the intestine. We also map gene regulatory differences in these cells that are suggestive of a regulatory differentiation cascade, and associate intestinal disease heritability with specific cell types. These results describe the complexity of the cell composition, regulation and organization for this organ, and serve as an important reference map for understanding human biology and disease.

  View details for DOI 10.1038/s41586-023-05915-x

  View details for PubMedID 37468586

  View details for PubMedCentralID PMC10356619

• Serine biosynthesis as a novel therapeutic target for dilated cardiomyopathy. European heart journal Perea-Gil, I., Seeger, T., Bruyneel, A. A., Termglinchan, V., Monte, E., Lim, E. W., Vadgama, N., Furihata, T., Gavidia, A. A., Arthur Ataam, J., Bharucha, N., Martinez-Amador, N., Ameen, M., Nair, P., Serrano, R., Kaur, B., Feyen, D. A., Diecke, S., Snyder, M. P., Metallo, C. M., Mercola, M., Karakikes, I. 2022

  Abstract

  AIMS: Genetic dilated cardiomyopathy (DCM) is a leading cause of heart failure. Despite significant progress in understanding the genetic aetiologies of DCM, the molecular mechanisms underlying the pathogenesis of familial DCM remain unknown, translating to a lack of disease-specific therapies. The discovery of novel targets for the treatment of DCM was sought using phenotypic sceening assays in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) that recapitulate the disease phenotypes in vitro.METHODS AND RESULTS: Using patient-specific iPSCs carrying a pathogenic TNNT2 gene mutation (p.R183W) and CRISPR-based genome editing, a faithful DCM model in vitro was developed. An unbiased phenotypic screening in TNNT2 mutant iPSC-derived cardiomyocytes (iPSC-CMs) with small molecule kinase inhibitors (SMKIs) was performed to identify novel therapeutic targets. Two SMKIs, Go 6976 and SB 203580, were discovered whose combinatorial treatment rescued contractile dysfunction in DCM iPSC-CMs carrying gene mutations of various ontologies (TNNT2, TTN, LMNA, PLN, TPM1, LAMA2). The combinatorial SMKI treatment upregulated the expression of genes that encode serine, glycine, and one-carbon metabolism enzymes and significantly increased the intracellular levels of glucose-derived serine and glycine in DCM iPSC-CMs. Furthermore, the treatment rescued the mitochondrial respiration defects and increased the levels of the tricarboxylic acid cycle metabolites and ATP in DCM iPSC-CMs. Finally, the rescue of the DCM phenotypes was mediated by the activating transcription factor 4 (ATF4) and its downstream effector genes, phosphoglycerate dehydrogenase (PHGDH), which encodes a critical enzyme of the serine biosynthesis pathway, and Tribbles 3 (TRIB3), a pseudokinase with pleiotropic cellular functions.CONCLUSIONS: A phenotypic screening platform using DCM iPSC-CMs was established for therapeutic target discovery. A combination of SMKIs ameliorated contractile and metabolic dysfunction in DCM iPSC-CMs mediated via the ATF4-dependent serine biosynthesis pathway. Together, these findings suggest that modulation of serine biosynthesis signalling may represent a novel genotype-agnostic therapeutic strategy for genetic DCM.

  View details for DOI 10.1093/eurheartj/ehac305

  View details for PubMedID 35728000

• A cancer-associated RNA polymerase III identity drives robust transcription and expression of snaR-A noncoding RNA. Nature communications Van Bortle, K., Marciano, D. P., Liu, Q., Chou, T., Lipchik, A. M., Gollapudi, S., Geller, B. S., Monte, E., Kamakaka, R. T., Snyder, M. P. 2022; 13 (1): 3007

  Abstract

  RNA polymerase III (Pol III) includes two alternate isoforms, defined by mutually exclusive incorporation of subunit POLR3G (RPC7alpha) or POLR3GL (RPC7beta), in mammals. The contributions of POLR3G and POLR3GL to transcription potential has remained poorly defined. Here, we discover that loss of subunit POLR3G is accompanied by a restricted repertoire of genes transcribed by Pol III. Particularly sensitive is snaR-A, a small noncoding RNA implicated in cancer proliferation and metastasis. Analysis of Pol III isoform biases and downstream chromatin features identifies loss of POLR3G and snaR-A during differentiation, and conversely, re-establishment of POLR3G gene expression and SNAR-A gene features in cancer contexts. Our results support a model in which Pol III identity functions as an important transcriptional regulatory mechanism. Upregulation of POLR3G, which is driven by MYC, identifies a subgroup of patients with unfavorable survival outcomes in specific cancers, further implicating the POLR3G-enhanced transcription repertoire as a potential disease factor.

  View details for DOI 10.1038/s41467-022-30323-6

  View details for PubMedID 35637192

• Epigenomic Disruption of Cardiovascular Care What It Will Take CIRCULATION RESEARCH Monte, E., Fischer, M. A., Vondriska, T. M. 2017; 120 (11): 1692–93

  View details for PubMedID 28546346

  View details for PubMedCentralID PMC5527682