Epigenetic Programmers Targeted During Developmental Reprogramming

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，以增加以后生命中对疾病的易感性，这一过程被称为发育重新编程。发育重编程被认为是通过破坏表观基因组发生的，现在被认为会增加成年后患代谢性疾病的风险，包括肥胖、糖尿病、心血管疾病和癌症。我们是第一个确定非基因组(或者更准确地说是前基因组)信号是内分泌干扰化学物质(EDCs)扰乱表观遗传机制并诱导发育重新编程的直接机制。激活基因组前信号通路中的磷酸化阅读器、写入器和擦除器的激酶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，在我们对表观基因组机制如何在发育重编程过程中被前基因组信号扰乱的理解中，仍然存在巨大的知识缺口。我们不知道：1)哪些超越PI3K/AKT的激酶/前基因组信号通路被肝脏(或其他组织)中的“肥胖源”激活；2)哪些表观基因组编程器是这些激酶的靶标，或磷酸化(或其他PTM)如何改变它们的活性(上调或下调)；也不知道3)重新编程的基因上的哪些特定表观遗传学“标记”被改变，以改变基因表达，增加成年后肥胖(或其他疾病)的易感性。这项应用的目标是通过详细的机械理解来填补这些知识空白，了解内分泌细胞如何利用前基因组信号来扰乱表观基因组，并更好地了解这种发育重新编程如何改变肝脏中的新陈代谢“设定点”以促进肥胖。

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.