A Positive Regulatory Role for the mSin3A-HDAC Complex in Pluripotency through Nanog and Sox2

Abstract

Large networks of proteins govern embryonic stem (ES) cell pluripotency. Recent analysis of the critical pluripotency factors Oct4 and Nanog has identified their interaction with multiple transcriptional repression complexes, including members of the mSin3A-HDAC complex, suggesting that these factors could be involved in the regulation of Oct4/Nanog function. mSin3A is critical for embryonic development, but the mechanism by which the mSin3A-HDAC complex is able to regulate ES cell pluripotency is undefined. Herein we show that the mSin3A-HDAC complex positively regulates Nanog expression in ES cells through Sox2, a critical ES cell transcription factor and regulator of Nanog. We have identified the mSin3A-HDAC complex to be present at the Nanog promoter only under proliferating conditions concurrent with histone acetylation. We find that Sox2 associates with mSin3A-HDAC complex members both in vitro and in vivo, similar to the interactions found between Oct4/Nanog and the mSin3A-HDAC complex. Knockdown of mSin3A-HDAC complex members or HDAC inhibitor treatment reduces Nanog expression, and overexpression of mSin3A-HDAC complex subunits stimulates Nanog expression. Our data demonstrate that the mSin3A-HDAC complex can positively regulate Nanog expression under proliferating conditions and that this activity is complementary to mSin3A-mediated p53-dependent silencing of Nanog during differentiation.

Differentiation and upregulation of heat shock protein 70 induced by a subset of histone deacetylase inhibitors in mouse and human embryonic stem cells

“…2A). These results agreed with pre-http://bmbreports.org BMB reports (8,11). Recently, it was reported that a repressor complex including mSin3A, HDAC1, and HDAC2 is involved in ES cell maintenance (11).…”

Sin3a-associated Hdac1 and Hdac2 are essential for hematopoietic stem cell homeostasis and contribute differentially to hematopoiesis

“…Hdac1, Hdac2 and Sin3a were found in complex with Nanog, Sox2 and Oct4 in a transcription regulatory complex known as Nanog and Oct4 associated deacetylase (NODE), which regulated Nanog expression. [31][32][33] In line with this it was shown that HDAC inhibitors can enhance the formation of induced pluripotent stem cells, probably by derepression of critical pluripotency regulators, including Nanog, Oct4 and Klf4. 34 Alternatively, since Hdac1 was found at predominantly active genes in embryonic stem cells and early thymocytes it is also possible that Hdac1 is required for activation of regulators of self-renewal.…”

Histone deacetylase (HDAC) 1 and 2 are essential for accurate cell division and the pluripotency of embryonic stem cells

“…Deletion of LSD1 perturbs the CoREST complex but does not affect Oct4 expression (39), whereas loss of MBD3 (central component of NuRD) prevents Oct4 from being repressed at all, even under differentiating conditions (40). By process of elimination, this suggests that the Sin3A complex may positively regulate Oct4 and Nanog expression; and indeed Baltus et al (41) were able to demonstrate a direct role for the Sin3A/HDAC complex in the activation of the Nanog promoter. More recently, a genome-wide promoter analysis in ES cells revealed that HDAC1 binds close to the transcriptional start site of many pluripotent factors, including Oct4, Nanog, Sox2, and Rex1 (7), again suggesting a positive role in the maintenance of cell self-renewal.…”