Embryonic Stem Cells and Gene Regulation
Dr. Raja Jothi, Head, Systems Biology Group
National Institute of Environmental Health Sciences (NIEHS)
National Institutes of Health (NIH)
Embryonic stem cells (ESCs) maintain an epigenetic state that enables both self-renewal and differentiation into all embryonic lineages. Thus, they could one day be exploited for transplantation therapies where a population of cells compromised by a disease/injury could be replaced with new functional cells. Successful development of such therapies would require a complete understanding of the transcriptional program that maintains the pluripotent genome in a stable state of self-renewal, while allowing rapid induction of alternate transcriptional programs to initiate differentiation. Focused functional as well as high throughput analysis have revealed that Oct4, Sox2, Nanog, and Klf4 form the core transcriptional circuitry in ESCs to stably maintain the expression of pluripotency genes, and to repress lineage determinant genes. RNAi screens of about 16K genes in mouse ESCs (by 3 studies) collectively have revealed ~400 other genes with roles in ESC maintenance. While these genome-wide screens were similarly designed and targeted more or less the same set of genes, there is almost no agreement between the sets of genes reported as required for ESC maintenance. The presence of unique hits in each study suggests none of these screens have reached saturation and that many additional genes with roles in ESC maintenance remain to be discovered. I will first present an approach for identifying novel regulators required for mouse embryonic stem cell maintenance. Second, I will present unpublished data showing that STAT3, downstream transcription factor of LIF signaling, is targeted to its sites across the pluripotent genome by esBAF, a specialized ATP-dependent chromatin remodeling complex essential for ESC self-renewal and pluripotency.