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: 8726398
• 负责人: MARK T. BEDFORD
• 金额: $ 52.26万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8726398
• 关键词: Acute; Adult; Back; Binding; Biochemical; Cardiovascular Diseases; Cell Culture Techniques; Cells; ChIP-seq; Code; Coenzyme A; Complement; Complex; Computer Simulation; DNA; Development; Diabetes Mellitus; Disease; Elderly; Endocrine Disruptors; Epigenetic Process; Exposure to; Gene Expression; Gene Targeting; Genes; Genetic; Genomics; Goals; Image; Image Analysis; Knowledge; Life; Liver; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Messenger RNA; Metabolic; Metabolic Diseases; Methods; Modeling; Neonatal; Nuclear Hormone Receptors; Nuclear Translocation; Obesity; PI3K/AKT; Peroxisome Proliferator-Activated Receptors; Phospho-Specific Antibodies; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Post-Translational Protein Processing; Predisposition; Process; RXR; Reader; Reagent; Recruitment Activity; Risk; Signal Pathway; Signal Transduction; Site; Technology; Tertiary Protein Structure; Testing; TimeLine; Tissues; Visual; Writing; base; chromatin modification; chromatin remodeling; critical period; environmental stressor; epigenome; epigenomics; experience; exposed human population; histone acetyltransferase; histone methyltransferase; innovation; liver metabolism; non-genomic; novel; obesogen; programs; promoter; public health relevance; response; tool; transcriptome sequencing

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应激源可以永久性地重新编程正常的生理反应，以增加以后生活中对疾病的易感性，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发生的，现在被认为会增加成年期代谢疾病的风险，包括肥胖症，糖尿病，心血管疾病和癌症。我们是第一个将非基因组（或更准确地说是前基因组）信号转导作为内分泌干扰物（EDCs）破坏表观遗传机制并诱导发育重编程的直接机制。激活前基因组信号通路中的激酶，使阅读器、写入器和擦除器磷酸化，作为环境应激源参与细胞表观遗传机制的中心机制是非常有吸引力的。然而，我们对发育重编程期间前基因组信号如何破坏表观基因组机制的理解仍然存在巨大的知识差距。我们不知道：1）哪些激酶/PI 3 K/AKT以外的前基因组信号通路被肝脏中的“肥胖原”激活（或其他组织）; 2）哪些表观基因组程序员被这些激酶靶向或如何磷酸化（或其他PTM）改变其活性（向上或向下）;或3）哪些特定的表观遗传“标记”被置于重编程基因上，从而改变基因表达并增加对肥胖的易感性（或其他疾病）。本申请的目标是通过详细了解EDC如何利用前基因组信号传导来破坏表观基因组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。