TrxG complexes in pancreas endocrine-cell specification

胰腺内分泌细胞规范中的 TrxG 复合物

• 批准号: RGPIN-2016-04292
• 负责人: Hoffman, Brad
• 金额: $ 2.4万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=685111
• 关键词: TrxG; complexes; pancreas; endocrine; cell

Transcriptional regulation is a critical component of pancreas lineage specification and maturation. Despite this the specific mechanisms by which transcription factors involved in this process are regulate are not well understood. Epigenetic factors, which include DNA methylation and histone modifications are central mediators of transcriptional regulation. Our previous data indicated that many of the transcription factors necessary for endocrine and exocrine lineage commitment need to gain an active chromatin state, and/or to remove repressive histone modifications to become expressed. We hypothesized that these changes were catalyzed by trithorax group (TrxG) complexes. TrxG complexes all contain the core proteins Ash2l, Dpy30, Rbbp5, and Wdr5 that are critical to their assembly and/or function. Thus to test our hypothesis that this complex was necessary for the induction of transcription factors necessary for endocrine and exocrine lineage commitment we knocked-out the core component Dpy30 in pancreas progenitors. Our preliminary data suggests that in these mice specification of pancreas progenitors into both endocrine and exocrine lineages is severely compromised.***Based on these preliminary data we hypothesize that: (a) Loss of Dpy30 impairs the ability of pancreas multipotent progenitors cells to be specified into exocrine progenitors, and that Dpy30 is necessary for exocrine cells to be maintain their mature state; (b) Loss of Dpy30 in endocrine precursors will prevent the normal induction of proendocrine transcription factors, and (c) that TrxG complexes are recruited to the cis-regulatory regions by interactions with pancreas critical transcription factors and/or by as yet unidentified pancreas endocrine progenitor specific lncRNAs. To test these hypotheses, we propose the following objectives over the five-year term of this grant.***Objective 1: To determine the role of the TrxG complex in endocrine progenitor specification.***Objective 2: To determine the role of the TrxG complex in exocrine cell specification and maturation state.***Objective 3: To determine how the TrxG complex gets recruited to endocrine and exocrine specific cis-regulatory loci.***These studies will provide valuable insight into how pancreas progenitors become specified into the different pancreas endocrine and exocrine cell types, and determine the role of the TrxG complex in this process. Specifically, this work will address whether the TrxG complex is necessary to allow the induction of the transcriptional cascades that drive the development and maintenance of these cell types. **

转录调控是胰腺谱系规范和成熟的关键组成部分。尽管如此，参与这一过程的转录因子的具体调节机制尚不清楚。表观遗传因素，包括 DNA 甲基化和组蛋白修饰，是转录调控的核心介质。我们之前的数据表明，内分泌和外分泌谱系定型所需的许多转录因子需要获得活跃的染色质状态，和/或去除抑制性组蛋白修饰才能表达。我们假设这些变化是由三胸群（TrxG）复合物催化的。 TrxG 复合物均含有对其组装和/或功能至关重要的核心蛋白 Ash2l、Dpy30、Rbbp5 和 Wdr5。因此，为了检验我们的假设，即该复合物对于诱导内分泌和外分泌谱系定型所需的转录因子是必需的，我们敲除胰腺祖细胞中的核心成分 Dpy30。我们的初步数据表明，在这些小鼠中，胰腺祖细胞分化为内分泌和外分泌谱系的能力受到严重损害。***根据这些初步数据，我们假设：(a) Dpy30 的缺失会损害胰腺多能祖细胞分化为外分泌祖细胞的能力，并且 Dpy30 是外分泌细胞维持其成熟所必需的 状态; (b) 内分泌前体中 Dpy30 的缺失将阻止原内分泌转录因子的正常诱导，(c) TrxG 复合物通过与胰腺关键转录因子和/或尚未鉴定的胰腺内分泌祖细胞特异性 lncRNA 的相互作用而被招募到顺式调控区域。为了检验这些假设，我们在该资助的五年期限内提出以下目标。***目标 1：确定 TrxG 复合物在内分泌祖细胞规范中的作用。***目标 2：确定 TrxG 复合物在外分泌细胞规范和成熟状态中的作用。***目标 3：确定 TrxG 复合物如何招募到内分泌和外分泌特异性顺式调节位点。***这些研究将提供 深入了解胰腺祖细胞如何分化为不同的胰腺内分泌和外分泌细胞类型，并确定 TrxG 复合物在此过程中的作用。具体来说，这项工作将解决 TrxG 复合物是否是诱导转录级联所必需的，从而驱动这些细胞类型的发育和维持。 **