Suhas Srinivasan, Ph.D.

All Publications

• irCLIP-RNP and Re-CLIP reveal patterns of dynamic protein associations on RNA. bioRxiv : the preprint server for biology Ducoli, L., Zarnegar, B. J., Porter, D. F., Meyers, R. M., Miao, W., Riley, N. M., Srinivasan, S., Jackrazi, L. V., Yang, Y. Y., Li, Z., Wang, Y., Bertozzi, C. R., Flynn, R. A., Khavari, P. A. 2024

  Abstract

  RNA binding proteins ( RBPs ) control varied processes, including RNA splicing, stability, transport, and translation 1-3 . Dysfunctional RNA-RBP interactions contribute to the pathogenesis of human disease 1,4,5 , however, characterizing the nature and dynamics of multiprotein assemblies on RNA has been challenging. To address this, non-isotopic ligation-based ultraviolet crosslinking immunoprecipitation 6 was combined with mass spectrometry ( irCLIP-RNP ) to identify RNA-dependent associated proteins ( RDAPs ) co-bound to RNA with any RBP of interest. irCLIP-RNP defined landscapes of multimeric protein assemblies on RNA, uncovering previously unknown patterns of RBP-RNA associations, including cell-type-selective combinatorial relationships between RDAPs and primary RBPs. irCLIP-RNP also defined dynamic RDAP remodeling in response to epidermal growth factor ( EGF ), uncovering EGF-induced recruitment of UPF1 adjacent to HNRNPC to effect splicing surveillance of cell proliferation mRNAs. To identify the RNAs simultaneously co-bound by multiple studied RBPs, a sequential immunoprecipitation irCLIP ( Re-CLIP ) method was also developed. Re-CLIP confirmed binding relationships seen in irCLIP-RNP and detected simultaneous HNRNPC and UPF1 co-binding on RND3 and DDX3X mRNAs. irCLIP-RNP and Re-CLIP provide a framework to identify and characterize dynamic RNA-protein assemblies in living cells.

  View details for DOI 10.1101/2024.09.27.615518

  View details for PubMedID 39386644

  View details for PubMedCentralID PMC11463378

• Mitochondrial Raf1 Regulates Glutamine Catabolism. bioRxiv : the preprint server for biology Shanderson, R. L., Ferguson, I. D., Siprashvili, Z., Ducoli, L., Li, A. M., Miao, W., Srinivasan, S., Velasco, M. G., Li, Y., Ye, J., Khavari, P. A. 2024

  Abstract

  Raf kinases play vital roles in normal mitogenic signaling and cancer, however, the identities of functionally important Raf-proximal proteins throughout the cell are not fully known. Raf1 proximity proteomics/BioID in Raf1-dependent cancer cells unexpectedly identified Raf1-adjacent proteins known to reside in the mitochondrial matrix. Inner-mitochondrial localization of Raf1 was confirmed by mitochondrial purification and super-resolution microscopy. Inside mitochondria, Raf1 associated with glutaminase (GLS) in diverse human cancers and enabled glutaminolysis, an important source of biosynthetic precursors in cancer. These impacts required Raf1 kinase activity and were independent of canonical MAP kinase pathway signaling. Kinase-dead mitochondrial matrix-localized Raf1 impaired glutaminolysis and tumorigenesis in vivo. These data indicate that Raf1 localizes inside mitochondria where it interacts with GLS to engage glutamine catabolism and support tumorigenesis.

  View details for DOI 10.1101/2024.03.08.581297

  View details for PubMedID 38496616

  View details for PubMedCentralID PMC10942467

• Xist ribonucleoproteins promote female sex-biased autoimmunity. Cell Dou, D. R., Zhao, Y., Belk, J. A., Zhao, Y., Casey, K. M., Chen, D. C., Li, R., Yu, B., Srinivasan, S., Abe, B. T., Kraft, K., Hellström, C., Sjöberg, R., Chang, S., Feng, A., Goldman, D. W., Shah, A. A., Petri, M., Chung, L. S., Fiorentino, D. F., Lundberg, E. K., Wutz, A., Utz, P. J., Chang, H. Y. 2024; 187 (3): 733-749.e16

  Abstract

  Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long non-coding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex comprising numerous autoantigenic components is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multi-organ pathology in a pristane-induced lupus model than wild-type males. Xist expression in males reprogrammed T and B cell populations and chromatin states to more resemble wild-type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity.

  View details for DOI 10.1016/j.cell.2023.12.037

  View details for PubMedID 38306984

• The Extent of Edgetic Perturbations in the Human Interactome Caused by Population-Specific Mutations. Biomolecules Cui, H., Srinivasan, S., Gao, Z., Korkin, D. 2023; 14 (1)

  Abstract

  Until recently, efforts in population genetics have been focused primarily on people of European ancestry. To attenuate this bias, global population studies, such as the 1000 Genomes Project, have revealed differences in genetic variation across ethnic groups. How many of these differences can be attributed to population-specific traits? To answer this question, the mutation data must be linked with functional outcomes. A new "edgotype" concept has been proposed, which emphasizes the interaction-specific, "edgetic", perturbations caused by mutations in the interacting proteins. In this work, we performed systematic in silico edgetic profiling of ~50,000 non-synonymous SNVs (nsSNVs) from the 1000 Genomes Project by leveraging our semi-supervised learning approach SNP-IN tool on a comprehensive set of over 10,000 protein interaction complexes. We interrogated the functional roles of the variants and their impact on the human interactome and compared the results with the pathogenic variants disrupting PPIs in the same interactome. Our results demonstrated that a considerable number of nsSNVs from healthy populations could rewire the interactome. We also showed that the proteins enriched with interaction-disrupting mutations were associated with diverse functions and had implications in a broad spectrum of diseases. Further analysis indicated that distinct gene edgetic profiles among major populations could shed light on the molecular mechanisms behind the population phenotypic variances. Finally, the network analysis revealed that the disease-associated modules surprisingly harbored a higher density of interaction-disrupting mutations from healthy populations. The variation in the cumulative network damage within these modules could potentially account for the observed disparities in disease susceptibility, which are distinctly specific to certain populations. Our work demonstrates the feasibility of a large-scale in silico edgetic study, and reveals insights into the orchestrated play of population-specific mutations in the human interactome.

  View details for DOI 10.3390/biom14010040

  View details for PubMedID 38254640

• Unravelling psychiatric heterogeneity and predicting suicide attempts in women with trauma-related dissociation using artificial intelligence EUROPEAN JOURNAL OF PSYCHOTRAUMATOLOGY Srinivansan, S., Harnett, N. G., Zhang, L., Dahlgren, M., Jang, J., Lu, S., Nephew, B. C., Palermo, C. A., Pan, X., Eltabakh, M. Y., Frederick, B. B., Gruber, S. A., Kaufman, M. L., King, J., Ressler, K. J., Winternitz, S., Korkin, D., Lebois, L. M. 2022; 13 (2)

  View details for DOI 10.1080/20008066.2022.2143693

  View details for Web of Science ID 000889608300001

• Computational protein modeling and the next viral pandemic NATURE METHODS Narykov, O., Srinivasan, S., Korkin, D. 2021; 18 (5): 439-440

  View details for DOI 10.1038/s41592-021-01144-0

  View details for Web of Science ID 000648344900010

  View details for PubMedID 33963340

• Structural Genomics and Interactomics of SARS-COV2: Decoding Basic Building Blocks of the Coronavirus Virus Bioinformatics Gao, Z., Lu, S., Narykov, O., Srinivasan, S., Korkin, D. Chapman and Hall/CRC. 2021; 1: 121-139
• A hybrid deep clustering approach for robust cell type profiling using single-cell RNA-seq data RNA Srinivasan, S., Leshchyk, A., Johnson, N. T., Korkin, D. 2020; 26 (10): 1303-1319

  Abstract

  Single-cell RNA sequencing (scRNA-seq) is a recent technology that enables fine-grained discovery of cellular subtypes and specific cell states. Analysis of scRNA-seq data routinely involves machine learning methods, such as feature learning, clustering, and classification, to assist in uncovering novel information from scRNA-seq data. However, current methods are not well suited to deal with the substantial amount of noise that is created by the experiments or the variation that occurs due to differences in the cells of the same type. To address this, we developed a new hybrid approach, deep unsupervised single-cell clustering (DUSC), which integrates feature generation based on a deep learning architecture by using a new technique to estimate the number of latent features, with a model-based clustering algorithm, to find a compact and informative representation of the single-cell transcriptomic data generating robust clusters. We also include a technique to estimate an efficient number of latent features in the deep learning model. Our method outperforms both classical and state-of-the-art feature learning and clustering methods, approaching the accuracy of supervised learning. We applied DUSC to a single-cell transcriptomics data set obtained from a triple-negative breast cancer tumor to identify potential cancer subclones accentuated by copy-number variation and investigate the role of clonal heterogeneity. Our method is freely available to the community and will hopefully facilitate our understanding of the cellular atlas of living organisms as well as provide the means to improve patient diagnostics and treatment.

  View details for DOI 10.1261/rna.074427.119

  View details for Web of Science ID 000570798100002

  View details for PubMedID 32532794

  View details for PubMedCentralID PMC7491323

• Structural Genomics of SARS-CoV-2 Indicates Evolutionary Conserved Functional Regions of Viral Proteins VIRUSES-BASEL Srinivasan, S., Cui, H., Gao, Z., Liu, M., Lu, S., Mkandawire, W., Narykov, O., Sun, M., Korkin, D. 2020; 12 (4)

  Abstract

  During its first two and a half months, the recently emerged 2019 novel coronavirus, SARS-CoV-2, has already infected over one-hundred thousand people worldwide and has taken more than four thousand lives. However, the swiftly spreading virus also caused an unprecedentedly rapid response from the research community facing the unknown health challenge of potentially enormous proportions. Unfortunately, the experimental research to understand the molecular mechanisms behind the viral infection and to design a vaccine or antivirals is costly and takes months to develop. To expedite the advancement of our knowledge, we leveraged data about the related coronaviruses that is readily available in public databases and integrated these data into a single computational pipeline. As a result, we provide comprehensive structural genomics and interactomics roadmaps of SARS-CoV-2 and use this information to infer the possible functional differences and similarities with the related SARS coronavirus. All data are made publicly available to the research community.

  View details for DOI 10.3390/v12040360

  View details for Web of Science ID 000539525300002

  View details for PubMedID 32218151

  View details for PubMedCentralID PMC7232164

• Enriching Human Interactome with Functional Mutations to Detect High-Impact Network Modules Underlying Complex Diseases GENES Cui, H., Srinivasan, S., Korkin, D. 2019; 10 (11)

  Abstract

  Rapid progress in high-throughput -omics technologies moves us one step closer to the datacalypse in life sciences. In spite of the already generated volumes of data, our knowledge of the molecular mechanisms underlying complex genetic diseases remains limited. Increasing evidence shows that biological networks are essential, albeit not sufficient, for the better understanding of these mechanisms. The identification of disease-specific functional modules in the human interactome can provide a more focused insight into the mechanistic nature of the disease. However, carving a disease network module from the whole interactome is a difficult task. In this paper, we propose a computational framework, Discovering most IMpacted SUbnetworks in interactoMe (DIMSUM), which enables the integration of genome-wide association studies (GWAS) and functional effects of mutations into the protein-protein interaction (PPI) network to improve disease module detection. Specifically, our approach incorporates and propagates the functional impact of non-synonymous single nucleotide polymorphisms (nsSNPs) on PPIs to implicate the genes that are most likely influenced by the disruptive mutations, and to identify the module with the greatest functional impact. Comparison against state-of-the-art seed-based module detection methods shows that our approach could yield modules that are biologically more relevant and have stronger association with the studied disease. We expect for our method to become a part of the common toolbox for the disease module analysis, facilitating the discovery of new disease markers.

  View details for DOI 10.3390/genes10110933

  View details for Web of Science ID 000502296000099

  View details for PubMedID 31731769

  View details for PubMedCentralID PMC6895925

• Assessment of network module identification across complex diseases NATURE METHODS Choobdar, S., Ahsen, M. E., Crawford, J., Tomasoni, M., Fang, T., Lamparter, D., Lin, J., Hescott, B., Hu, X., Mercer, J., Natoli, T., Narayan, R., Aicheler, F., Amoroso, N., Arenas, A., Azhagesan, K., Baker, A., Banf, M., Batzoglou, S., Baudot, A., Bellotti, R., Bergmann, S., Boroevich, K. A., Brun, C., Cai, S., Caldera, M., Calderone, A., Cesareni, G., Chen, W., Chichester, C., Cowen, L., Cui, H., Phuong Dao, De Domenico, M., Dhroso, A., Didier, G., Divine, M., del Sol, A., Feng, X., Flores-Canales, J. C., Fortunato, S., Gitter, A., Gorska, A., Guan, Y., Guenoche, A., Gomez, S., Hamza, H., Hartmann, A., He, S., Heijs, A., Heinrich, J., Hu, Y., Huang, X., Hughitt, V., Jeon, M., Jeub, L., Johnson, N. T., Joo, K., Joung, I., Jung, S., Kalko, S. G., Kamola, P. J., Kang, J., Kaveelerdpotjana, B., Kim, M., Kim, Y., Kohlbacher, O., Korkin, D., Krzysztof, K., Kunji, K., Kutalik, Z., Lage, K., Lang-Brown, S., Thuc Duy Le, Lee, J., Lee, S., Lee, J., Li, D., Li, J., Liu, L., Loizou, A., Luo, Z., Lysenko, A., Ma, T., Mall, R., Marbach, D., Mattia, T., Medvedovic, M., Menche, J., Micarelli, E., Monaco, A., Mueller, F., Narykov, O., Norman, T., Park, S., Perfetto, L., Perrin, D., Pirro, S., Przytycka, T. M., Qian, X., Raman, K., Ramazzotti, D., Ramsahai, E., Ravindran, B., Rennert, P., Saez-Rodriguez, J., Scharfe, C., Sharan, R., Shi, N., Shin, W., Shu, H., Sinha, H., Slonim, D. K., Spinelli, L., Srinivasan, S., Subramanian, A., Suver, C., Szklarczyk, D., Tangaro, S., Thiagarajan, S., Tichit, L., Tiede, T., Tripathi, B., Tsherniak, A., Tsunoda, T., Turei, D., Ullah, E., Vahedi, G., Valdeolivas, A., Vivek, J., von Mering, C., Waagmeester, A., Wang, B., Wang, Y., Weir, B. A., White, S., Winkler, S., Xu, K., Xu, T., Yan, C., Yang, L., Yu, K., Yu, X., Zaffaroni, G., Zaslavskiy, M., Zeng, T., Zhang, J. D., Zhang, L., Zhang, W., Zhang, L., Zhang, X., Zhang, J., Zhou, X., Zhou, J., Zhu, H., Zhu, J., Zuccon, G., Stolovitzky, G., Kutalik, Z., Lage, K., Slonim, D. K., Saez-Rodriguez, J., Cowen, L. J., Bergmann, S., Marbach, D., DREAM Module Identification Ch 2019; 16 (9): 843-+

  Abstract

  Many bioinformatics methods have been proposed for reducing the complexity of large gene or protein networks into relevant subnetworks or modules. Yet, how such methods compare to each other in terms of their ability to identify disease-relevant modules in different types of network remains poorly understood. We launched the 'Disease Module Identification DREAM Challenge', an open competition to comprehensively assess module identification methods across diverse protein-protein interaction, signaling, gene co-expression, homology and cancer-gene networks. Predicted network modules were tested for association with complex traits and diseases using a unique collection of 180 genome-wide association studies. Our robust assessment of 75 module identification methods reveals top-performing algorithms, which recover complementary trait-associated modules. We find that most of these modules correspond to core disease-relevant pathways, which often comprise therapeutic targets. This community challenge establishes biologically interpretable benchmarks, tools and guidelines for molecular network analysis to study human disease biology.

  View details for DOI 10.1038/s41592-019-0509-5

  View details for Web of Science ID 000484044700022

  View details for PubMedID 31471613

  View details for PubMedCentralID PMC6719725