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Modulation of HDAC activity directly reprogramme embryonic stem cell to trophoblast stem cell [bulk RNA-Seq]

ABSTRACT: Embryonic stem cells (ESCs) can differentiate into all cell types of each of the embryonic germ layers. ESCs can also generate totipotent 2C-like cells and trophectodermal cells. However, these latter transitions occur at low frequency due to epigenetic barriers, the nature of which are not fully understood. Here, we show that mouse ESCs treated with sodium butyrate, an HDAC inhibitor, have a greatly increased 2C-like cell population and can transdifferentiate into trophoblast stem cells (TSCs). Interestingly, this ESC to TSC transition is a direct reprogramming event that does not require transition through a 2C-like state. Mechanistically, butyrate inhibits Class I histone deacetylases activities in LSD1-HDAC1/2 corepressor complex, increasing acetylation levels in the regulatory regions of 2C and TSC specific genes. Importantly, butyrate treated cells acquire the capacity to generate blastocyst-like structures that can develop beyond the implantation stage in vitro and induce decidualization in vivo. These results uncover how epigenetic changes can expand the potency of ESCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE193082 | GEO | 2024/03/18

REPOSITORIES: GEO

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Modulation of HDAC activity directly reprogramme embryonic stem cell to trophoblast stem cell [ChIP-Seq]

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Project description:A small subgroup of embryonic stem cells (ESCs) exhibit molecular features similar to those of two-cell embryos (2C). Multiple chromatin modifiers associated with H3K9 trimethylation (H3K9me3) have been implicated in the mediation of the 2C-like transition. However, it remains elusive how H3K9me3 is remodeled and its association with totipotent cells. Here, we analyze the genome-wide change in H3K9me3 in 2C-like transitions. We revealed that a large fraction of trophoblast-stem-cell specific enhancers undergoes loss of H3K9me3 exclusively in MERVL+/Zscan4+ cells during 2C-like transitions.

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The totipotent 2C-like state safeguards genomic stability of mouse embryonic stem cells

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