Assistant Professor, Cell and Regenerative Biology, Epigenetics
- 330 North Orchard Street
- Madison WI 53715
- Room 2118
- 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.
- Sridharan, R. and Plath, K. (2011) Small RNAs loom large during reprogramming. Cell Stem Cell 8, 599-601
- 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
- Sridharan, R. and Plath, K. (2008) Illuminating the black box of reprogramming. Cell Stem Cell 2, 295-297
- 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