Pluripotency transcription factor Oct4 mediates stepwise nucleosome demethylation and depletion.

Mol Cell Biol
Authors
Keywords
Abstract

The mechanisms whereby the crucial pluripotency transcription factor Oct4 regulates target gene expression are incompletely understood. Using an assay system based on partially differentiated embryonic stem cells, we show that Oct4 opposes the accumulation of local H3K9me2 and subsequent Dnmt3a-mediated DNA methylation. Upon binding DNA, Oct4 recruits the histone lysine demethylase Jmjd1c. Chromatin immunoprecipitation (ChIP) time course experiments identify a stepwise Oct4 mechanism involving Jmjd1c recruitment and H3K9me2 demethylation, transient FACT (facilitates chromatin transactions) complex recruitment, and nucleosome depletion. Genome-wide and targeted ChIP confirms binding of newly synthesized Oct4, together with Jmjd1c and FACT, to the Pou5f1 enhancer and a small number of other Oct4 targets, including the Nanog promoter. Histone demethylation is required for both FACT recruitment and H3 depletion. Jmjd1c is required to induce endogenous Oct4 expression and fully reprogram fibroblasts to pluripotency, indicating that the assay system identifies functional Oct4 cofactors. These findings indicate that Oct4 sequentially recruits activities that catalyze histone demethylation and depletion.

Year of Publication
2015
Journal
Mol Cell Biol
Volume
35
Issue
6
Pages
1014-25
Date Published
2015 Mar
ISSN
1098-5549
URL
DOI
10.1128/MCB.01105-14
PubMed ID
25582194
PubMed Central ID
PMC4333097
Links
Grant list
P50 HG006193 / HG / NHGRI NIH HHS / United States
R01 AI100873 / AI / NIAID NIH HHS / United States
R01AI100873 / AI / NIAID NIH HHS / United States