Years at WID2012 - present
- B.S., St. Xavier’s College, Mumbai, India
- M.S., University of Baroda, India
- Ph.D., University of California, Los Angeles
- Postdoctoral Research, Eli and Edythe Broad Stem Cell Institute, UCLA
Epigenetics of cell fate change
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:
- How do the reprogramming factors activate pluripotency loci?
- What controls the global chromatin structure during reprogramming?
- 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.
- Zaidan NZ, Walker KJ, Brown JE, Schaffer LV, Scalf M, Shortreed MR, Iyer G, Smith LM, Sridharan R.Compartmentalization of HP1 Proteins in Pluripotency Acquisition and Maintenance.Stem Cell Reports.2018 Feb 13;10(2):627-641. doi: 10.1016/j.stemcr.2017.12.016. PMID: 29358085
- Buxton KE, Kennedy-Darling J, Shortreed MR, Zaidan NZ, Olivier M, Scalf M, Sridharan R, Smith LM. Elucidating Protein-DNA Interactions in Human Alphoid Chromatin via Hybridization Capture and Mass Spectrometry.J Proteome Res. 2017 Sep 1;16(9):3433-3442. doi: 10.1021/acs.jproteome.7b00448. Epub 2017 Aug 4. PMID: 28704058
- 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.
- 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
- 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