Dynamics of genomic H3K27me3 domains and role of EZH2 during pancreatic endocrine specification. (8th August 2014)

• Record Type: Journal Article
• Authors: Xu, Cheng‐Ran; Li, Lin‐Chen; Donahue, Greg; Ying, Lei; Zhang, Yu‐Wei; Gadue, Paul; Zaret, Kenneth S
• Is Part Of: EMBO journal. Volume 33:Number 19(2014)
• Page Start: 2157
• Page End: 2170
• Publication Date: 2014-08-08
• Subjects: Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201488671
• Languages: English
• ISSNs: 0261-4189

Abstract

<abstract abstract-type="main" id="embj201488671-abs-0001"> <title>Abstract</title> <p>Endoderm cells undergo sequential fate choices to generate insulin‐secreting beta cells. <italic>Ezh2</italic> of the PRC2 complex, which generates H3K27me3, modulates the transition from endoderm to pancreas progenitors, but the role of <italic>Ezh2</italic> and H3K27me3 in the next transition to endocrine progenitors is unknown. We isolated endoderm cells, pancreas progenitors, and endocrine progenitors from different staged mouse embryos and analyzed H3K27me3 genome‐wide. Unlike the decline in H3K27me3 domains reported during embryonic stem cell differentiation <italic>in vitro</italic>, we find that H3K27me3 domains increase in number during endocrine progenitor development <italic>in vivo</italic>. Genes that lose the H3K27me3 mark typically encode transcriptional regulators, including those for pro‐endocrine fates, whereas genes that acquire the mark typically are involved in cell biology and morphogenesis. Deletion of <italic>Ezh2</italic> at the pancreas progenitor stage enhanced the production of endocrine progenitors and beta cells. Inhibition of EZH2 in embryonic pancreas explants and in human embryonic stem cell cultures increased endocrine progenitors <italic>in vitro</italic>. Our studies reveal distinct dynamics in H3K27me3 targets <italic>in vivo</italic> and a means to modulate beta cell development from stem cells.</p> </abstract>