Nanog and Oct4 associate with unique transcriptional repression complexes in embryonic stem cells

Abstract

Nanog and Oct4 are essential transcription factors that regulate self-renewal and pluripotency of ES cells. However, the mechanisms by which Nanog and Oct4 modulate ES cell fate remain unknown. Through characterization of endogenous Nanog and Oct4 protein complexes in mouse ES cells, we found that these transcription factors interact with each other and associate with proteins from multiple repression complexes, including the NuRD, Sin3A and Pml complexes. In addition, Nanog, Oct4 and repressor proteins co-occupy Nanog-target genes in mouse ES cells, suggesting that Nanog and Oct4 together may communicate with distinct repression complexes to control gene transcription. To our surprise, of the various core components in the NuRD complex with which Nanog and Oct4 interact, Mta1 was preferred, whereas Mbd3 and Rbbp7 were either absent or present at sub-stoichiometric levels. We named this unique Hdac1/2- and Mta1/2-containing complex NODE (for Nanog and Oct4 associated deacetylase). Interestingly, NODE contained histone deacetylase (HDAC) activity that seemed to be comparable to NuRD, and retained its association with Nanog and Oct4 in Mbd3(-/-) ES cells. In contrast to Mbd3 loss-of-function, knockdown of NODE subunits led to increased expression of developmentally regulated genes and ES-cell differentiation. Our data collectively suggest that Nanog and Oct4 associate with unique repressor complexes on their target genes to control ES cell fate.

Defective Myofibroblast Formation from Mesenchymal Stem Cells in the Aging Murine Heart

“…Nanog and Oct3/4 associate with histone deacetylase in repression complexes by which they control gene transcription and prevent differentiation. 50 In contrast, methylation (down-regulation) of Oct3/4 and Nanog promoters was demonstrated in embryonic stem cells on differentiation. 51 Bmp2 expression is increased in aged MSCs, consistent with the role of this protein in adipogenesis and with the preadipocytic phenotype of the aged cells.…”

HDAC1 and HDAC2 in mouse oocytes and preimplantation embryos: Specificity versus compensation

“…HDAC1 and HDAC2 lack a DNA-binding domain, as do all deacetylases, and execute their function by interacting with transcription factors as either homo-or heterodimers, or being part of multi-component repressor complexes. 8,9 The best characterized HDAC1/2-containing complexes in mammals are the SIN3 co-repressor complex, 23 nucleosome remodeling and deacetylase (NuRD) complex, 24 CoREST complex, 25 Nanog and Oct4 (POU5F1)-associated deacetylase complex that is specifically found in embryonic stem (ES) cells, 26 and PRC2 complex. 27 The ubiquitous expression, high deacetylase activity toward common substrates and high homology between HDAC1 and HDAC2 suggest that each could compensate for loss of function of the other.…”

OCT4: Less is more

“…The importance of transcriptional networks in the ES cell has been well documented, however recently laboratories have begun to investigate the proteomic interactions and signaling events that mediate these networks [4,5]. In this issue of Cell Res, a report by Xu et al [6] becomes the first to characterize a post-translational regulation event occurring on OCT4 in a hES cell system.…”