Rupa Sridharan

Address: Room 2118 Wisconsin Institute for Discovery – 330 N. Orchard Street – Madison, WI 53715

Visit the Sridharan lab webpage

PubMed

Education

B.Sc., St. Xavier’s College, University of Mumbai, India
M.Sc., M.S. University of Baroda, India
Ph.D., University of California, Los Angeles
Postdoctoral Research, Eli and Edythe Broad Stem Cell Institute, UCLA

Research

Embryonic stem (ES) cells have the ability to divide indefinitely and to differentiate into any tissue under the correct set of chemical stimuli. Transcription factor- mediated reprogramming, initially demonstrated in mouse somatic cells, is the process by which the overexpression of a few transcription factors, usually, Oct4, Sox2, c-Myc and Klf4 converts differentiated cells into induced pluripotent stem (iPS) cells. Multiple molecular and functional studies have shown that iPS cells are highly similar to ES cells. Human somatic cells can also be reprogrammed, providing iPS cells both as tools for translational research such as for in vitro drug screens and for cell replacement therapy. Only about 1 % of cells complete the reprogramming process suggesting that multiple barriers have to be overcome for this dramatic change in cell fate to occur. Research in the lab will be focused on understanding the epigenetic roadblocks to the reprogramming process to illuminate both the mechanisms that control pluripotency and the stability of the differentiated state.

Specifically, we want to answer the following questions: 1. How do the reprogramming factors activate pluripotency loci? 2. What controls the global chromatin structure during reprogramming? 3. Are there common principles in the reversion of differentiation that can be applied to switching the lineage between two differentiated cell types?

Insights from these basic research studies may enable the rational development of more efficient methods of reprogramming somatic cells for use in therapeutic settings.

Representative Publications

• Wille CK, Sridharan R. DOT1L inhibition enhances pluripotency beyond acquisition of epithelial identity and without immediate suppression of the somatic transcriptome. Stem Cell Reports. 2022 Feb 8;17(2):384-396. doi: 10.1016/j.stemcr.2021.12.004. Epub 2022 Jan 6. PMID: 34995500; PMCID: PMC8828533.
• Zaidan NZ, Sridharan R. HP1γ regulates H3K36 methylation and pluripotency in embryonic stem cells. Nucleic Acids Res. 2020 Dec 16;48(22):12660-12674. doi: 10.1093/nar/gkaa1091. PMID: 33237287; PMCID: PMC7736818.
• Lee H, Lee YS, Harenda Q, Pietrzak S, Oktay HZ, Schreiber S, Liao Y, Sonthalia S, Ciecko AE, Chen YG, Keles S, Sridharan R, Engin F. Beta Cell Dedifferentiation Induced by IRE1α Deletion Prevents Type 1 Diabetes. Cell Metab. 2020 Apr 7;31(4):822-836.e5. doi: 10.1016/j.cmet.2020.03.002. Epub 2020 Mar 26.PMID: 32220307
• Haws SA, Yu D, Ye C, Wille CK, Nguyen LC, Krautkramer KA, Tomasiewicz JL, Yang SE, Miller BR, Liu WH, Igarashi K, Sridharan R, Tu BP, Cryns VL, Lamming DW, Denu JM. Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence. Mol Cell. 2020 Apr 16;78(2):210-223.e8. doi: 10.1016/j.molcel.2020.03.004. Epub 2020 Mar 23.PMID: 32208170
• Tran, K.A., Pietrzak, S.P, Zaidan, N.Z., Siahpirani, A.F., McKalla S.G., Iyer, G., Roy,S., and Sridharan, R. (2019) Defining reprogramming checkpoints from single-cell analysis of induced pluripotency Cell Reports 27(6):1726-1741
• Tran, K.A., Dillingham, C.D. and Sridharan, R. (2019) Coordinated removal of repressive epigenetic modifications during induced reversal of cell identity EMBO J- e101681. doi: 10.15252/embj.2019101681
• Tran, K.A., Dillingham C., and Sridharan R. (2019) Role of alpha-KG dependent enzymes in reprogramming and pluripotency. J.  Biol. Chem, 294(14):5408-5419
• Zaidan, N.Z., Walker, K.J., Brown, J.E., Scalf, M., Shortreed, M., Smith, L.M., Iyer, G., and Sridharan, R. (2018) Compartmentalization of HP1 proteins in pluripotency acquisition and maintenance. Stem Cell Reports, 10 (2): 627–641.
• Roy S, Sridharan R. Chromatin module inference on cellular trajectories identifies key transition points and poised epigenetic states in diverse developmental processes. Genome Res. 2017 Jul;27(7):1250-1262.
• Jackson SA, Olufs ZP, Tran KA, Zaidan NZ, Sridharan R. (2016) Alternative Routes to Induced Pluripotent Stem Cells Revealed by Reprogramming of the Neural Lineage. Stem Cell Reports. 6:302-11.

• Roy S, Siahpirani AF, Chasman D, Knaack S, Ay F, Stewart R, Wilson M, Sridharan R. (2016) A predictive modeling approach for cell line-specific long-range regulatory interactions. Nucleic Acids Res. 44:1977-8.

• Tran, K.A., Jackson, S.A., Olufs, Z.P.G., Zaidan, N.Z., Leng, N., Kendziorski, C., Roy, S., and Sridharan, R. (2015) Collaborative rewiring of the pluripotency network by chromatin and signaling modulating pathways. Nat Commun. 6:6188. doi: 10.1038/ncomms7188. Link
• Jackson, S.A. and Sridharan, R. (2013) The nexus of Tet1 and the pluripotency network. Cell Stem Cell 12, 387-88
• Jackson, S.A. and Sridharan, R. (2013) Peering into the black box of reprogramming to the pluripotent state. Curr Pathobiol Rep, 1,129-136

• Britton LM, Newhart A, Bhanu NV, Sridharan R, Gonzales-Cope M, Plath K, Janicki SM, Garcia BA. (2013) Initial characterization of histone H3 serine 10 O-acetylation. Epigenetics. 2013 8:1101-13.
• Sridharan, R., Gonzales-Cope, M., Chronis, C.,Bonora, G., McKee, R., Patel,S., Lopez,D., Mishra, N., Pellegrini, M., Carey, M., Garcia, B.A. and Plath, K. (2013) Proteomic and genomic approaches reveal critical functions of H3K9 methylation and Heterochromatin Protein-1g in reprogramming to pluripotency. Nat Cell Bio doi10.1038/ncb2768
• Sridharan R *., Tchieu J *., Mason M.J. *. , Yachechko R., Kuoy E., Horvath S., Zhou Q. and Plath K. (2009). Role of the murine reprogramming factors in the induction of pluripotency. * authors contributed equally to this work. Cell 136 (2), 364-77
• Maherali, N.*, Sridharan, R.*, Xie, W., Utikal, J., Eminli, S., Arnold, K., Stadtfeld, M., Yachechko, R., Tchieu. J., Jaenisch, R., Plath, K.#, and Hochedlinger, K.# (2007). Global epigenetic remodeling in directly reprogrammed fibroblasts. * both authors contributed equally to this work; # co-corresponding authors. Cell Stem Cell 1, 55-70
• Lowry, W. E., Richter, L .,Yachechko, R., Pyle, A. D., Tchieu, J. ,Sridharan, R., Clark, A. T. and Plath, K.(2008) Generation of human induced pluripotent cells from dermal fibroblasts. PNAS 105, 2883-2888
• Xie, W., Song, C., Sperling, A., Xu, F., Sridharan, R., Conway, A., Plath, K., Clark, A.T. and Grunstein, M. (2009) Histone H3 K56 acetylation marks canonical histone genes and the core transcriptional network for pluripotency in human embryonic stem cells. Mol Cell 33(4), 417-27
• Gaspar-Maia, A., Alajem, A., Polesso, F., Sridharan, R., Mason, M.J., Heidersbach, A., Ramalho-Santos, J., McManus, M.T., Plath, K., Meshorer, E. and Ramalho-Santos, M. (2009) Chd1 regulates open chromatin and pluripotency of embryonic stem cells. Nature 460(7257), 863-8
• Lin, J.J., Lehmann, L.W., Bonora, G., Sridharan, R., Vashisht, A.A., Tran, N., Plath, K., Wohlschlegel, J.A., Carey, M. (2011) Mediator coordinates PIC assembly with recruitment of CHD1. Genes Dev 25, 2198-209