Epigenetic Programmers Targeted During Developmental Reprogramming

描述（由申请人提供）：细胞或组织在发育的关键时期暴露于环境压力源可以永久性地重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，并且现在被认为会增加成年期代谢性疾病的风险，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（或更准确地说是前基因组）信号作为内分泌干扰化学物质（EDCs）破坏表观遗传机制和诱导发育重编程的直接机制。基因组前信号通路中磷酸化读取器、写入器和擦除器的激酶的激活作为环境压力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，对于表观基因组机制在发育重编程过程中是如何被基因组前信号干扰的，我们的理解仍然存在巨大的知识缺口。我们不知道：1)哪些激酶/ PI3K/AKT以外的基因组前信号通路被肝脏（或其他组织）中的“肥胖原”激活；2)哪些表观基因组编程程序是这些激酶的目标，或者磷酸化（或其他PTMs）如何改变它们的活性（提高或降低）；3)重编程基因上的哪些特定的表观遗传“标记”被改变，从而改变基因表达，增加成年后对肥胖（或其他疾病）的易感性。本应用程序的目标是通过对EDCs如何利用基因组前信号破坏表观基因组的详细机制理解来填补这些知识空白，并更好地理解这种发育重编程如何改变肝脏中的代谢“设值点”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.