Chromatin contacts are germline-transmissable vehicles underlying epigenetic transgenerational inheritance

在动物模型中的研究将孕期暴露于内分泌干扰物(EDCs)与 暴露者和未暴露者子代发病。许多研究小组发现了这种跨代效应 化学暴露，这被认为是表观遗传的例子。跨代 环境暴露的影响在文献中得到了实质性的支持。然而，对此做出回应的概念 环境暴露可以通过没有DNA的生殖系传递给后代。 突变仍然存在争议，因为潜在的机制还没有得到令人满意的解释。 了解环境暴露的影响如何在没有DNA的情况下传递给未暴露的后代 突变是生物学中一个基本的、尚未解答的问题。我们培育出了一种高度可复制的动物 肥胖的跨代遗传模型。当怀孕的F0小鼠被用来治疗的时候 在怀孕期间通过饮用水摄入与环境相关的(NM)剂量的TBT，会增加脂肪 在F1-F4代雄性后代中检测到积累。受影响的TBT组男性患上 代际“节俭表现型”：他们在禁食期间抵抗脂肪流失，在禁食后体重迅速增加 即使回到正常的低脂肪饮食，饮食中的脂肪也会增加并保留下来。我们出版的 初步结果使我们提出了一种新的跨代遗传模式--产前TBT 暴露改变了高阶染色质结构(HOCS)，改变了次级表观遗传修饰物 抑制胰岛素降解酶(IDE)的表达，导致饮食诱导的高胰岛素血症和肥胖。 在这里，我们提出了一系列全面的实验，旨在确切地确定暴露于 怀孕的F0母猪的TBT改变了F1-F3原始生殖细胞(PGC)的HOCS，为什么这些变化是 继承，而不是逆转到正常状态，这些变化如何影响较低水平的表观遗传调控 控制IDE的表达，以及为什么这种表型只出现在男性身上。目标1将确定机制 这一驱动因素改变了IDE基因附近的HOCS，以及这些HOCS如何与较低水平的表观遗传调控因子相互作用 调节IDE在成人肝脏中的表达。目标2测试表观遗传干预，如溶解 改变HOCS或释放抑制PGC或成体的IDE表达可防止或逆转 男性特有代谢表型的跨代易感性。破译潜在的 机制将对该领域如何看待跨代继承以及如何 未来的实验是计划和进行的。这一新的理解将对解释 肥胖症和2型糖尿病等非传染性疾病的病因学，针对其病因和 改善它们的效果。我们的结果将对理解表观遗传传播具有广泛的意义。 环境应激源的影响，并可提供机会纳入考虑预防 将跨代遗传纳入风险评估范式。

Studies in animal models linked gestational exposures to endocrine disrupting chemicals (EDCs) with the onset of disease in exposed and unexposed descendants. Many groups found such transgenerational effects of chemical exposures, which were proposed to be examples of epigenetic inheritance. Transgenerational effects of environmental exposures have substantial support in the literature. Yet the concept that responses to environmental exposures can be transmitted to subsequent generations through the germline without DNA mutations remains controversial because the underlying mechanisms have not been explained satisfactorily. Understanding how effects of environmental exposures are transmitted to unexposed generations without DNA mutations is a fundamental, unanswered question in biology. We developed a highly reproducible animal model for transgenerational inheritance of obesity. When pregnant F0 mouse dams were treated with environmentally-relevant (nM) doses of TBT via their drinking water throughout gestation, increased fat accumulation was detected in F1-F4 generation male descendants. Affected TBT-group males developed a transgenerational “thrifty phenotype”: they were resistant to fat loss during fasting, rapidly gained weight when dietary fat was increased and retained this fat even after being returned to a normal, low-fat diet. Our published and preliminary results led us to propose a new model for transgenerational inheritance - that prenatal TBT exposure altered higher-order chromatin structure (HOCS), changing secondary epigenetic modifiers that inhibited expression of insulin degrading enzyme (Ide) causing diet-induced hyperinsulinemia and obesity. Here we propose a comprehensive series of experiments designed to determine exactly how exposure of pregnant F0 dams to TBT alters HOCS in F1-F3 primordial germ cells (PGCs), why these changes are inherited, rather than reversed to the normal state, how these changes affect lower-level epigenetic regulators controlling expression of Ide and why does the phenotype only occur in males. Aim 1 will identify mechanisms that drive changes HOCS near the Ide gene and how these interact with lower-level epigenetic regulators to modulate Ide expression in the adult liver. Aim 2 tests whether epigenetic interventions, such as dissolving the HOCS alterations or releasing Ide expression from repression in PGCs or adults can prevent or reverse the transgenerational predisposition to male-specific metabolic phenotypes. Deciphering the underlying mechanisms will have profound implications for how the field views transgenerational inheritance and how future experiments are planned and conducted. This new understanding will be critical to explaining the etiology of non-communicable diseases such as obesity and type 2 diabetes, targeting their causes and ameliorating their effects. Our results will have broad implications for understanding epigenetic transmission of the effects of environmental stressors and could offer opportunities to incorporate considering prevention of transgenerational inheritance into risk assessment paradigms.