Epigenetic Programmers Targeted During Developmental Reprogramming

表观遗传程序员是发育重编程过程中的目标

• 批准号: 9412709
• 负责人: MARK T. BEDFORD
• 金额: $ 47.91万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9412709
• 关键词: Epigenetic; Programmers; Targeted; During; Developmental

DESCRIPTION (provided by applicant): Exposure of cells or tissues to environmental stressors during critical periods of development can permanently reprogram normal physiological responses to increase susceptibility to disease later in life, a process termed developmental reprogramming. Developmental reprogramming is thought to occur via disruption of the epigenome, and is now appreciated to increase risk in adulthood for metabolic diseases, including obesity, diabetes, cardiovascular disease, and cancer. We were the first to identify non-genomic (or more accurately pre-genomic) signaling as a direct mechanism for endocrine disrupting chemicals (EDCs) to disrupt the epigenetic machinery and induce developmental reprogramming. Activation of kinases in pre-genomic signaling pathways that phosphorylate readers, writers and erasers is extremely attractive as a central mechanism for environmental stressors to engage the cell's epigenetic machinery. However, tremendous knowledge gaps remain in our understanding of how the epigenomic machinery is disrupted by pre-genomic signaling during developmental reprogramming. We do not know: 1) Which kinases/pre-genomic signaling pathways beyond PI3K/AKT are activated by "obesogens" in the liver (or other tissues); 2) Which epigenomic programmers are targeted by these kinases or how phosphorylation (or other PTMs) modifies their activity (up or down); nor 3) Which specific epigenetic "marks" placed on reprogrammed genes are altered to change gene expression and increase susceptibility to obesity (or other diseases) in adulthood. The goal of this application i to fill these knowledge gaps with a detailed mechanistic understanding of how EDCs utilize pre-genomic signaling to disrupt the epigenome, and to better understand how this developmental reprogramming alters metabolic "set-points" in the liver to promote obesity.

描述（由申请人提供）：在关键发育期间，将细胞或组织暴露于环境压力源可以永久重编程正常生理反应，以增加生命后期对疾病的易感性，这一过程称为发育重编程。人们认为发育重编程被认为是通过上依性基因组的破坏而发生的，现在被赞赏可以增加代谢疾病（包括肥胖，糖尿病，心血管疾病和癌症）的成年风险。我们是第一个识别非基因组（或更准确地基因前）信号传导作为内分泌破坏化学物质（EDC）的直接机制，以破坏表观遗传机制并诱导发育重编程。激活磷酸化读取器，作家和橡皮擦的基因组信号传导途径中的激活非常有吸引力，作为环境压力源使细胞表观遗传机制吸引的中心机制。但是，我们对在发育重编程过程中基因组信号传导如何破坏表观基因组机械如何破坏表观基因组机械的理解中仍然存在巨大的知识差距。我们不知道：1）在肝脏（或其他组织）中，哪些激酶/基因组信号通路被PI3K/AKT以外的途径激活； 2）这些激酶对哪些表观基因组分组者的靶向或磷酸化（或其他PTM）如何修饰其活性（向上或向下）；也没有3）在成年期间改变了在重编程基因上放置哪些特定表观遗传“标记”以改变基因表达并增加对肥胖症（或其他疾病）的敏感性。该应用程序I的目的是通过对EDC如何利用基因组信号传导来破坏表观基因组的详细机械理解来填补这些知识差距，并更好地理解这种发展重编程如何改变肝脏中的代谢“固定点”来促进肥胖。

项目成果

Methyllysine reader plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1) antagonizes DNA (cytosine-5) methyltransferase 1 (DNMT1) proteasomal degradation.

• DOI: 10.1074/jbc.m113.525279
• 发表时间: 2014-03-21
• 期刊: The Journal of biological chemistry
• 作者: Estève PO;Terragni J;Deepti K;Chin HG;Dai N;Espejo A;Corrêa IR Jr;Bedford MT;Pradhan S
• 通讯作者: Pradhan S