TrxG complexes in pancreas endocrine-cell specification

点击翻译按钮获取中文摘要

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. **