BioProject

Changing the somatic cell transcriptome to a pluripotent state using exogenous reprogramming factors needs transcriptional co-regulators that help activate or suppress gene expression and rewrite the epigenome. More...

Changing the somatic cell transcriptome to a pluripotent state using exogenous reprogramming factors needs transcriptional co-regulators that help activate or suppress gene expression and rewrite the epigenome. Here, we show that reprogramming-specific engagement of the NCoR/SMRT co-repressor complex at key pluripotency loci creates an epigenetic block to reprogramming. HDAC3 executes the repressive function of NCoR/SMRT in reprogramming by inducing histone deacetylation at these loci. Recruitment of NCoR/SMRT-HDAC3 to pluripotency genes is facilitated by all 4 Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) but mostly by c-MYC. Class IIa HDACs further potentiate this recruitment by interacting with both the reprogramming factors and NCoR/SMRT. Consequently, depleting NCoR/SMRT-HDAC3 function enables high efficiency of reprogramming, while elevating NCoR/SMRT-HDAC3 recruitment at pluripotency loci by over-expressing constitutively active class IIa HDACs derails it. Our findings thus uncover an unexpected epigenetic mechanism involving c-MYC, whose manipulation greatly enhances reprogramming efficiency. Overall design: RNA-seq data consisting of Oct4, Sox2, Klf4, c-Myc (OSKM) transfected mouse embryonic fibroblasts co-transfected with one of shRNA targetting Luciferase (control), Ncor1 (NCoR) or Ncor2 (SMRT). Cells were assayd for total RNA on days 5 and day 9. Less...