Chromatin contacts are germline-transmissable vehicles underlying epigenetic transgenerational inheritance

染色质接触是表观遗传跨代遗传的种系可传递载体

基本信息

批准号：
10745221
负责人：
BRUCE BLUMBERG
金额：
$ 66.05万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10745221
关键词：
Adipocytes Adult Affect Animal Model Animals Automobile Driving Biological Biology Cell Count Cell Separation ChIP-seq Chemical Exposure Chemicals Chromatin Chromatin Structure Alteration Clinical Clustered Regularly Interspaced Short Palindromic Repeats Consumption DNA DNA Sequence Alteration DNA-Binding Proteins Data Desire for food Diet Dietary Fats Disease Dose Embryo Endocrine Disruptors Environment Environmental Exposure Environmental Risk Factor Enzymes Epigenetic Process Etiology Experimental Designs Experimental Models Exposure to Fasting Fat-Restricted Diet Fatty acid glycerol esters Future Future Generations Gene Expression Generations Goals Health Health Care Costs Hi-C Higher Order Chromatin Structure Human Hyperglycemia Hyperinsulinism Inherited Insulin Resistance Insulinase Intervention Knockout Mice Lactation Life Link Literature Liver Memory Messenger RNA Metabolic Diseases Metabolism Modeling Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Proteins Nuclear Receptors Obesity Onset of illness Outcome Phenocopy Phenotype Play Predisposition Pregnancy Prevention Productivity Public Health Publishing Repression Reproducibility Research Resistance Risk Assessment Rodent Role Satiation Series Structure of primordial sex cell Techniques Technology Testing adult obesity bisphenol A design disease transmission drinking water energy balance environmental stressor epigenomics experimental study genome analysis hormone regulation human model insight mRNA Expression male men&apos s group metabolic phenotype mouse model obesity prevention obesogen pandemic disease phthalates pregnant prenatal prevent rapid weight gain response transgenerational epigenetic inheritance transmission process tributyltin

项目摘要

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.

动物模型的研究将妊娠暴露与内分泌破坏化学物质（EDC）与暴露和意外后代的疾病发作。许多小组发现这种变革效应化学暴露，被认为是表观遗传遗传的例子。转变环境暴露的影响在文献中得到了大量支持。然而，回应的概念环境暴露可以通过没有DNA的种系传输到后代突变仍然存在争议，因为尚未满足基本机制。了解如何将环境暴露的影响传播到没有DNA的未暴露的世代突变是生物学中的基本，未解决的问题。我们开发了一种高度可重复的动物肥胖遗传的转化遗传模型。当怀孕的F0小鼠大坝接受治疗时环境与环境与TBT的剂量通过妊娠期间的饮用水剂量增加，脂肪增加在F1-F4生成的男性后代中检测到积累。受影响的TBT组男性发展跨代“节俭表型”：它们在禁食期间对脂肪降低具有抵抗力，当饮食脂肪也增加并保留了这种脂肪，即使恢复了正常的低脂饮食。我们出版了初步结果使我们提出了一个新的转化继承模型 - 产前TBT 暴露改变了高阶染色质结构（HOC），改变了次级表观遗传修饰剂，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，旨在确切确定如何暴露怀孕的F0大坝to tbt改变了F1-F3原始生殖细胞（PGC）中的HOC，为什么这些变化是这些变化遗传而不是逆转到正常状态，而是如何影响下层表观遗传调节剂控制IDE的表达，以及为什么表型仅发生在男性中。 AIM 1将确定机制这种驱动会改变IDE基因附近的HOC，以及它们如何与低级表观遗传调节剂相互作用调节成年肝脏中的IDE表达。 AIM 2测试表观遗传干预措施，例如溶解在PGC或成人中，HOC改变或从PGC中释放IDE表达可以防止或逆转跨代对男性代谢表型的倾向。破译基础机制将对现场如何看待变革性继承以及如何如何产生深远的影响计划和进行未来的实验。这种新的理解将是至关重要的肥胖和2型糖尿病等非通信疾病的病因，针对其原因和改善其影响。我们的结果将对理解表观遗传传播具有广泛的影响环境压力源的影响，可以提供机会，以纳入预防的考虑跨代遗传进入风险评估范例。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The unexpected teratogenicity of RXR antagonist UVI3003 via activation of PPARγ in Xenopus tropicalis.

DOI：
10.1016/j.taap.2016.11.014
发表时间：
2017-01-01
期刊：
TOXICOLOGY AND APPLIED PHARMACOLOGY
影响因子：
3.8
作者：
Zhu, Jingmin;Janesick, Amanda;Wu, Lijiao;Hu, Lingling;Tang, Weiyi;Blumberg, Bruce;Shi, Huahong
通讯作者：
Shi, Huahong

Parma consensus statement on metabolic disruptors.

DOI：
10.1186/s12940-015-0042-7
发表时间：
2015-06-20
期刊：
Environmental health : a global access science source
影响因子：
0
作者：
Heindel JJ;Vom Saal FS;Blumberg B;Bovolin P;Calamandrei G;Ceresini G;Cohn BA;Fabbri E;Gioiosa L;Kassotis C;Legler J;La Merrill M;Rizzir L;Machtinger R;Mantovani A;Mendez MA;Montanini L;Molteni L;Nagel SC;Parmigiani S;Panzica G;Paterlini S;Pomatto V;Ruzzin J;Sartor G;Schug TT;Street ME;Suvorov A;Volpi R;Zoeller RT;Palanza P
通讯作者：
Palanza P

Uppsala Consensus Statement on Environmental Contaminants and the Global Obesity Epidemic.

DOI：
10.1289/ehp.1511115
发表时间：
2016-05-01
期刊：
Environmental health perspectives
影响因子：
10.4
作者：
Lind L;Lind PM;Lejonklou MH;Dunder L;Bergman Å;Guerrero-Bosagna C;Lampa E;Lee HK;Legler J;Nadal A;Pak YK;Phipps RP;Vandenberg LN;Zalko D;Ågerstrand M;Öberg M;Blumberg B;Heindel JJ;Birnbaum LS
通讯作者：
Birnbaum LS

Obesogens: How They Are Identified and Molecular Mechanisms Underlying Their Action.