TrxG Complex Catalytic and Non-catalytic Activity Play Distinct Roles in Pancreas Progenitor Specification and Differentiation
TrxG Complex Catalytic and Non-catalytic Activity Play Distinct Roles in Pancreas Progenitor Specification and Differentiation
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DOI：
10.1016/j.celrep.2019.07.035
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发表时间：
2019-08-13
期刊：
影响因子：
8.8
通讯作者：
Hoffman, Brad G.
中科院分区：
文献类型：
--
作者：
Campbell, Stephanie A.;McDonald, Cassandra L.;Hoffman, Brad G.
胰腺发育需要适当调节协调胰腺祖细胞增殖和分化的基因。在这里，我们探讨了H3K4甲基化和TrxG复合物在胰腺发育过程中介导基因表达的作用。TrxG复合物组装的破坏，但不是催化活性，阻止胰腺祖细胞球状体中的内分泌细胞分化。体内PDX 1（+）细胞中TrxG催化活性的丧失增加了细胞凋亡和细胞周期G1期祖细胞的比例。胰腺祖细胞被重新分配到腺泡谱系，主要是以NEUROG 3（+）内分泌祖细胞为代价。在发育后期，腺泡和内分泌细胞数量减少，基因表达差异增加，腺泡细胞中末端标记物活化减少，导致其分化不完全。这些发现表明，TrxG共激活因子活性是基因诱导所必需的，而TrxG催化活性和H3K4甲基化有助于维持转录稳定性。
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.