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Cell Rep. 2019 Aug 13;28(7):1830-1844.e6. doi: 10.1016/j.celrep.2019.07.035.

TrxG Complex Catalytic and Non-catalytic Activity Play Distinct Roles in Pancreas Progenitor Specification and Differentiation.

Author information

1
Department of Surgery, University of British Columbia, Vancouver, BC V5Z 4E3, Canada; Diabetes Research Group, British Columbia Children's Hospital Research Institute, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
2
Department of Surgery, University of British Columbia, Vancouver, BC V5Z 4E3, Canada.
3
Department of Surgery, University of British Columbia, Vancouver, BC V5Z 4E3, Canada; Diabetes Research Group, British Columbia Children's Hospital Research Institute, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada. Electronic address: brad.hoffman@ubc.ca.

Abstract

Appropriate regulation of genes that coordinate pancreas progenitor proliferation and differentiation is required for pancreas development. Here, we explore the role of H3K4 methylation and the Trithorax group (TrxG) complexes in mediating gene expression during pancreas development. Disruption of TrxG complex assembly, but not catalytic activity, prevented endocrine cell differentiation in pancreas progenitor spheroids. In vivo loss of TrxG catalytic activity in PDX1+ cells increased apoptosis and the fraction of progenitors in the G1 phase of the cell cycle. Pancreas progenitors were reallocated to the acinar lineage, primarily at the expense of NEUROG3+ endocrine progenitors. Later in development, acinar and endocrine cell numbers were decreased, and increased gene expression variance and reduced terminal marker activation in acinar cells led to their incomplete differentiation. These findings demonstrate that TrxG co-activator activity is required for gene induction, whereas TrxG catalytic activity and H3K4 methylation help maintain transcriptional stability.

KEYWORDS:

DPY30; H3K4 methylation; TrxG complexes; WDR5; pancreas development; transcriptional variation

PMID:
31412250
DOI:
10.1016/j.celrep.2019.07.035
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