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）：在发育的关键时期，细胞或组织暴露于环境压力源可以永久地重新编程正常的生理反应，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。发育重编程被认为是通过表观基因组的破坏而发生的，现在人们认为它会增加成年后患代谢疾病的风险，包括肥胖、糖尿病、心血管疾病和癌症。我们是第一个发现非基因组（或更准确地说是前基因组）信号传导作为内分泌干扰化学物质（EDC）破坏表观遗传机制并诱导发育重编程的直接机制的人。激活前基因组信号通路中的激酶，使读取器、写入器和擦除器磷酸化，作为环境压力源参与细胞表观遗传机制的核心机制，极具吸引力。然而，我们对发育重编程过程中表观基因组机制如何被前基因组信号破坏的理解仍然存在巨大的知识差距。我们不知道： 1) PI3K/AKT 之外的哪些激酶/前基因组信号通路被肝脏（或其他组织）中的“致肥胖物质”激活； 2) 这些激酶针对哪些表观基因组程序员，或者磷酸化（或其他 PTM）如何改变其活性（上调或下调）； 3) 重编程基因上的哪些特定表观遗传“标记”被改变以改变基因表达并增加成年后对肥胖（或其他疾病）的易感性。该应用程序的目标是通过对 EDC 如何利用前基因组信号传导破坏表观基因组的详细机制了解来填补这些知识空白，并更好地了解这种发育重编程如何改变肝脏中的代谢“设定点”以促进肥胖。

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