GRHL2-Dependent Enhancer Switching Maintains a Pluripotent Stem Cell Transcriptional Subnetwork after Exit from Naive Pluripotency

Cell Stem Cell
Amy F ChenRobert Blelloch

Abstract

The enhancer landscape of pluripotent stem cells undergoes extensive reorganization during early mammalian development. The functions and mechanisms behind such reorganization, however, are unclear. Here, we show that the transcription factor GRHL2 is necessary and sufficient to activate an epithelial subset of enhancers as naive embryonic stem cells (ESCs) transition into formative epiblast-like cells (EpiLCs). Surprisingly, many GRHL2 target genes do not change in expression during the ESC-EpiLC transition. Instead, enhancers regulating these genes in ESCs diminish in activity in EpiLCs while GRHL2-dependent alternative enhancers become activated to maintain transcription. GRHL2 therefore assumes control over a subset of the naive network via enhancer switching to maintain expression of epithelial genes upon exit from naive pluripotency. These data evoke a model where the naive pluripotency network becomes partitioned into smaller, independent networks regulated by EpiLC-specific transcription factors, thereby priming cells for lineage specification.

Associated Datasets

Citations

Jun 22, 2019·Nature Communications·Charles C BellMark A Dawson
Dec 17, 2018·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·Felix J Boivin, Kai M Schmidt-Ott
Aug 14, 2020·Proceedings of the National Academy of Sciences of the United States of America·Carolyn Sangokoya, Robert Blelloch
Sep 4, 2020·International Journal of Molecular Sciences·Giuseppina DivisatoSilvia Parisi
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Jun 13, 2019·Cell Reports·Shen-Hsi YangAndrew D Sharrocks
Mar 2, 2021·Frontiers in Cell and Developmental Biology·Galym IsmagulovGuojun Sheng
Mar 11, 2021·Molecular Cell·Elizabeth D LarsonMelissa M Harrison
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Aug 24, 2021·Frontiers in Cell and Developmental Biology·Mengyi WeiSiqin Bao
Aug 17, 2021·Development·Nicola FestucciaPablo Navarro

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