Control of Islet Beta Specific PDX-1 and MafA Transcription

描述（由申请人提供）：胰十二指肠同源盒1 （Pdx1）基因编码一种转录因子（TF），该转录因子在胰腺早期发育和胰岛细胞的形成、维持和活性中至关重要。我们已经证明，Pdx1在胰腺祖细胞和分化的¿-细胞中的转录是由由区域I、II、III和IV定义的保守的5'侧序列驱动的，并且在小鼠中区域I-II-III的完全缺失导致严重的胰腺发育不全，类似于Pdx1基因的整体敲除。我们有强有力的证据表明，哺乳动物特有的II区是该区域的功能核心。区II的表观遗传结构将与直接调控的基因中的控制区进行比较

DESCRIPTION (provided by applicant): The pancreatic duodenal homeobox 1 (Pdx1) gene encodes a transcription factor (TF) that is essential in early pancreas development and later in the formation, maintenance and activity of islet ¿-cells. We have shown that Pdx1 transcription in pancreatic progenitors and differentiated ¿-cells is driven by conserved 5'-flanking sequences defined by Areas I, II, III and IV, and that complete deletion of Areas I-II-III in mice causes severe pancreas hypoplasia, similar to the global Pdx1 gene knockout. We have strong evidence that mammal-specific Area II is the functional core of this region. The epigenetic architecture of Area II will be compared to control regions in genes that are directly regulated by the Pdx1 protein. Area II is predicted to contain a poised epigenetic architecture in embryonic progenitors that produce little Pdx1 (termed Pdx1LO), which is subsequently modified as a prerequisite to high Pdx1 (Pdx1HI) production required for ¿-cell formation, differentiation and mature cell function. Moreover, we will determine how newly identified positive- and negative-acting Area II TFs impact ¿-cells. Strikingly, while transcriptional and chromatin-modifying networks are critical for functional ¿-cell production, it is unclear how these networks interact, and specifically what coregulators are recruited to remodel chromatin within the pancreas. We will test the hypothesis that our newly identified coregulators of Pdx1 profoundly influence Pdx1-mediated gene control. These findings will provide valuable insight into the transcriptional regulatory mechanisms that will be effective in the production of cellular therapeutics for diabetes treatment, for example by forward directed differentiation or reprogramming. PUBLIC HEALTH RELEVANCE: Several candidate and genome-wide studies have identified risk loci for type 2 diabetes; these genes include many transcription factors implicated in the control of ¿-cell development and function. Strikingly, the Pdx1 transcription factor is the only maturity onset diabetes of the young gene in which homozygous mutant humans have pancreatic agenesis, while heterozygotes develop early-onset diabetes due to islet ¿-cell dysfunction. Our proposed studies are designed to define the underlying transcriptional mechanisms through which Pdx1 and its associated coregulators influence ¿-cell maturation and adult cell function. We believe that our findings will be essential to the ongoing efforts to generate ¿-cells from ES, iPS and/or adult cell sources for type 1 diabetes treatment.