The SIN3A/HDAC Corepressor Complex Functionally Cooperates with NANOG to Promote Pluripotency

Although SIN3A is required for the survival of early embryos and embryonic stem cells (ESCs), the role of SIN3A in the maintenance and establishment of pluripotency remains unclear. Here, we find that the SIN3A/HDAC corepressor complex maintains ESC pluripotency and promotes the generation of induced pluripotent stem cells (iPSCs). Members of the SIN3A/HDAC corepressor complex are enriched in an extended NANOG interactome and function in transcriptional coactivation in ESCs. We also identified a critical role for SIN3A and HDAC2 in efficient reprogramming of somatic cells. Mechanistically, NANOG and SIN3A co-occupy transcriptionally active pluripotency genes in ESCs and also co-localize extensively at their genome-wide targets in pre-iPSCs. Additionally, both factors are required to directly induce a synergistic transcriptional program wherein pluripotency genes are activated and reprogramming barrier genes are repressed. Our findings indicate a transcriptional regulatory role for a major HDAC-containing complex in promoting pluripotency. [Display omitted] •NANOG and SIN3A co-occupy transcriptionally active pluripotency genes in ESCs•SIN3A has a stage-specific function during the reprogramming process•NANOG and SIN3A induce a transcriptional program that enhances reprogramming•HDAC2 is critical for the reprogramming-promoting function of SIN3A Saunders et al. describe the critical role of the SIN3A/HDAC corepressor complex in maintaining ESC pluripotency and promoting somatic cell reprogramming. NANOG and SIN3A co-occupy predominantly active genes in ESCs and also co-localize at the chromatin level in pre-iPSCs to directly activate pluripotency genes and repress reprogramming barrier genes.