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WIREs Syst Biol Med
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A systems view of epigenetic networks regulating pancreas development and β‐cell function

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Abstract The development of the pancreas and determination of endocrine cell fate are controlled by a highly complex interplay of signaling events and transcriptional networks. It is now known that an interconnected epigenetic program is also required to drive these processes. Recent studies using genome‐wide approaches have implicated epigenetic regulators, such as DNA and histone‐modifying enzymes and noncoding RNAs, to play critical roles in pancreas development and the maintenance of cell identity and function. Furthermore, genome‐wide analyses have implicated epigenetic changes as a casual factor in the pathogenesis of diabetes. In the future, genomic approaches to further our understanding of the role of epigenetics in endocrine cell development and function will be useful for devising strategies to produce or manipulate β‐cells for therapies of diabetes. WIREs Syst Biol Med 2015, 7:1–11. doi: 10.1002/wsbm.1287 This article is categorized under: Biological Mechanisms > Cell Fates Developmental Biology > Lineages Developmental Biology > Stem Cell Biology and Regeneration
Epigenetic programming of pancreatic lineage specification. Overview of the key steps in pancreas development and the role of epigenetic regulators in these transitions. As cells transition from an undifferentiated to a differentiated state, the chromatin undergoes cell type‐specific alterations that are highly regulated. For example, removal of the repressive mark H3K27me3 from promoters of endodermal regulators by the H3K27 demethylase JMJD3 results in endoderm induction. In foregut progenitor cells, loci for liver‐ and pancreas‐specific genes exhibit different chromatin pre‐patterns, and the histone methyltransferase EZH2 and the histone acetyltransferase p300 affect the cell fate choice between liver and pancreas. The differentiation of pancreatic progenitor cells into the different pancreatic cell types is influenced by histone deacetylases (HDACs) and EZH2.
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Epigenetic regulation in pancreatic endocrine differentiation and maintenance of β‐cell function. The diagram depicts the role of epigenetic regulators as endocrine progenitor cells differentiate into the different endocrine subtypes (a), in regulating cell plasticity (b), and β‐cell proliferation (c). (a) Histone deacetylase (HDAC) class I (HDAC‐I) and HDAC class IIa (HDAC‐IIa) family members have distinct effects on the development of individual endocrine cell types. (b) While genes critical for β‐cell function are expressed and marked by H3K4me3 in β‐cells, these same genes are silent and bivalently modified in α‐cells. This bivalency suggests a plastic epigenetic state for key β‐cell genes in α‐cells. Additionally, to maintain β‐cell identity, genes important for α‐cell function have to be actively repressed by the DNA methytransferases DNMT1 and DNMT3a in β‐cells. (c) Epigenetic modification of the Cdkn2 locus, encoding a cell cycle inhibitor, by BMI1 and EZH2 promotes β‐cell proliferation and regeneration, whereas the methyltransferase MLL1 contributes to β‐cell senescence.
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Developmental Biology > Stem Cell Biology and Regeneration
Developmental Biology > Lineages
Biological Mechanisms > Cell Fates

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