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. 2019 Nov 15;38(22):e101681.
doi: 10.15252/embj.2019101681. Epub 2019 Oct 4.

Coordinated Removal of Repressive Epigenetic Modifications During Induced Reversal of Cell Identity

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Free PMC article

Coordinated Removal of Repressive Epigenetic Modifications During Induced Reversal of Cell Identity

Khoa A Tran et al. EMBO J. .
Free PMC article

Abstract

Epigenetic modifications operate in concert to maintain cell identity, yet how these interconnected networks suppress alternative cell fates remains unknown. Here, we uncover a link between the removal of repressive histone H3K9 methylation and DNA methylation during the reprogramming of somatic cells to pluripotency. The H3K9me2 demethylase, Kdm3b, transcriptionally controls DNA hydroxymethylase Tet1 expression. Unexpectedly, in the absence of Kdm3b, loci that must be DNA demethylated are trapped in an intermediate hydroxymethylated (5hmC) state and do not resolve to unmethylated cytosine. Ectopic 5hmC trapping precludes the chromatin association of master pluripotency factor, POU5F1, and pluripotent gene activation. Increased Tet1 expression is important for the later intermediates of the reprogramming process. Taken together, coordinated removal of distinct chromatin modifications appears to be an important mechanism for altering cell identity.

Keywords: DNA demethylation; Kdm3b; chromatin crosstalk; iPSCs; reprogramming.

Conflict of interest statement

The authors declare that they have no conflict of interest.

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