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- Jain Laboratory
Associate Professor of Medicine and Cell & Developmental Biology
Perelman School of Medicine
Location: Smilow TRC 9-101
Admin: Emily Romick
Our overarching goal is to understand how cells establish and maintain their identity. We are particularly interested in how cardiac cell types are specified, and the implications of this process for diseases, including congenital heart disease and congestive heart failure. We leverage classic models of stem cell biology and readily work across disciplines to dissect the underpinnings of how genome organization shapes cell identity and fate. We work on this because it is not well understood how entire gene programs are coordinately enacted, such as those that happen as a cell progressively restricts. In addition, the promise of cell-based regenerative therapies requires the efficient generation of cells and tissues. We hope our studies will help add to the foundation for these efforts.
CELL IDENTITY | GENOME ORGANIZATION
The higher-order mechanisms that control cell fate are relatively poorly understood. It has become apparent that the genome is folded and organized in a stereotypical manner in three-dimensional space. We are interested in understanding how the organization of the genome in 3D space establishes and maintains cell identity. Our team focuses on the central hypothesis that the dynamic spatial distribution of the genome in the nucleus underlies establishment and maintenance of cell fate and that decoding the rules that instruct genome organization will inform how this is achieved. We are interested in:
- Discovery: Comprehensively defining how chromatin domains are spatially positioned across human lineages.
- Mechanism: Deciphering how spatial distribution of chromatin and genome folding shapes cell fate.
- Disease: Determining how nuclear architecture drives disease phenotypes.
We work across disciplines and collaborate with clinicians and scientists of all backgrounds to tackle our questions, using a combination of single-cell, next generation sequencing, live imaging, and proteomic approaches.
Linares-Saldana, R., Kim, W., Bolar, N., Zhang, H., Koch-Bojalad, B.A., Yoon, S., Shah, P. P., Karnay, A., Park, D.S., Luppino, J.M., Nguyen, S.C., Padamanabhan, A., Smith, C.L., Polseshko, A., Wang, Q., Li, L., Srivastava, D., Vahedi, G., Eom, G.H., Blobel, G.A., Joyce, E.F., Jain, R. BRD4 orchestrates genome folding to promote neural crest differentiation. Nature Genetics. 2021 Oct;53(10):1480-1492. doi: 10.1038/s41588-021-00934-8. Commentary in Nature Genetics.
Shah, P.P., Keough, K.C., Gjonia, K., Santini, G.T., Wickramasinghe, N.M., Dundes, C.E., Karnay, A., Chen, A., Salomon, R.E.A., Walsh, P.J., Nguyen, S.C., Whalen, S., Joyce, E.F., Loh, K.M., Dubois, N.C., Pollard, K.S., Jain, R.: An atlas of lamina-associated chromatin across twelve human cell types reveals an intermediate chromatin subtype. Genome Biology. 2023 Jan 23;24(1):16. doi: 10.1186/s13059-023-02849-5.
Shah, P.P., Lv, W., Rhoades, J.H., Poleshko, A., Abbey, D., Caporizzo, M.A., Heffler, J.G., Sayed, N., Thomas, D., Linares-Saldana, R., Wang, Q., Stanton, L.J., Bedi, K., Morley, M.P., Cappola, T.P., Owens, A.T., Margulies, K.B., Frank, D.B., Wu, J.C., Rader, D.J., Yang, W., Prosser, B.L., Musunuru, K., Jain, R. Pathogenic LMNA variants disrupt cardiac lamina-chromatin interactions and de-repress alternative fate genes. Cell Stem Cell. 2021 May 6;28(5):938-954.e9. doi: 10.1016/j.stem.2020.12.016. PubMed PMID: 33529599; PubMed Central PMCID: PMC8106635. Featured on NHLBI blog.
Poleshko, A., Shah, P.P., Gupta, M., Babu, A., Morley, M., Manderfield, L.J., Ifkovits, J.L., Calderon, D., Aghajanian, H., Pagan, J.S.P., Sun, Z., Wang, Q, Li, L., Dubois, N., Morrisey, E.E., Lazar, M.A., Smith, C.L., Epstein, J.A., Jain, R. Genome-nuclear lamina interactions regulate progenitor cell lineage restriction during cardiogenesis. Cell. 2017 Oct 19;171(3):573-587.
Padmanabhan, A., Alexanian, M., Linares-Saldana, R., Gonzalez-Teran, B., Andreoletti, G., Huang, Y., Connolly, A.J., Kim, W.K., Hsu, A., Duan, Q., Winchester, S., Haldar, S.M., Jain, R., Srivastava, D. BRD4 Interacts with GATA4 to Govern Mitochondrial Homeostasis in Adult Cardiomyocytes. Circulation. 2020 Dec 15;142(24):2338-2355. PMCID: PMC7736290. Co-corresponding senior author.
Mellis, I.A., Edelstein, H.I., Truitt, R., Goyal, Y., Beck, L.E., Symmons, O., Dunagin, M.C., Linares-Saldana, R.A., Shah, P.P., Pérez-Bermejo, J.A., Padmanabhan, A., Yang, W., Jain, R., Raj, A. Responsiveness to perturbations is a hallmark of transcription factors that maintain cell identity in vitro. Cell Syst. 2021 Jul 27;. doi: 10.1016/j.cels.2021.07.003. PubMed PMID: 34352221. Co-corresponding senior author.