Details

Autor(en) / Beteiligte

• Tran, Khoa A
• Dillingham, Caleb M
• Sridharan, Rupa

Titel

Coordinated removal of repressive epigenetic modifications during induced reversal of cell identity

Ist Teil von

• The EMBO journal, 2019-11, Vol.38 (22), p.e101681-n/a

Ort / Verlag

England: Blackwell Publishing Ltd

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. Synopsis Repressive epigenetic mechanisms are known to maintain cell fate, but whether they are coordinately removed during the acquisition of pluripotency remains poorly understood. Here, a functional regulatory link between Kdm3b‐mediated histone demethylation and Tet1 DNA demethylation is identified during the generation of induced pluripotent stem cells (iPSCs). Kdm3b is essential for the conversion of somatic cells and for full reprogramming of intermediate states to iPSCs. Lack of Kdm3b prevents Tet1 upregulation. In Kdm3b knockout cells, genomic loci are trapped in a DNA demethylation‐intermediate 5hmC state. Accumulation of 5hmC is incompatible with POU5F1 chromatin localization at shared loci. Generation of iPSCs involves a coordination of Kdm3b‐mediated histone demethylation and Tet1 DNA methylation activities.