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.
- Rupa Srudharan Named Shaw Scientist (2013)
- Rupa Sridharan Looks to Break Conversion Rate of Stem Cells
- 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) 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-1γ in reprogramming to pluripotency. Nat Cell Bio 15(7): 872-82.
- 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, 23;136(2):364-77.
- 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