Recruitment of CTCF to an Fto enhancer is responsible for transgenerational inheritance of BPA-induced obesity.
Recruitment of CTCF to an Fto enhancer is responsible for transgenerational inheritance of BPA-induced obesity.
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将CTCF募集到FTO增强子中是造成BPA诱导的肥胖症的跨代遗传的原因。
DOI：
10.1073/pnas.2214988119
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发表时间：
2022-12-13
影响因子：
11.1
通讯作者：
Corces, Victor G.
中科院分区：
文献类型：
--
作者：
Jung, Yoon Hee;Wang, Hsiao-Lin, V;Ruiz, Daniel;Bixler, Brianna J.;Linsenbaum, Hannah;Xiang, Jian-Feng;Forestier, Samantha;Shafik, Andrew M.;Jin, Peng;Corces, Victor G.
怀孕雌性小鼠暴露于双酚A（BPA）导致F2后代肥胖，这可以在没有额外暴露的情况下传递到F6代。肥胖是由食物消耗增加引起的，其传播与Fto基因内含子中存在的顺式调节元件（CRE）中的染色质可及位点的存在相关，Fto基因内含子在BPA暴露后变得去甲基化。这种CRE与Irx 3和Irx 5基因相互作用，这些基因参与下丘脑中食欲控制神经元的分化。携带CTCF位点缺失的小鼠在暴露于BPA后不会变得肥胖，这表明CTCF位点的表观遗传变化是肥胖跨代遗传的原因。环境诱导的表型在哺乳动物中通过转代传递的机制知之甚少。在这里，我们表明，怀孕的雌性小鼠暴露于双酚A（BPA）的F2后代肥胖的结果，由于食物摄入量增加。这种表观表型可以传递到F6代。对F1-F6代精子染色质可及性的分析显示，Fto基因的两个顺式调节元件（克雷斯）中含有CCCTC结合因子（CTCF）结合基序的位点发生了变化，这些位点与肥胖的传播相关。这些克雷斯显示肥胖小鼠精子中与Irx 3和Irx 5基因的相互作用增加，这些基因参与食欲控制神经元的分化。Fto中CTCF位点的缺失导致小鼠具有正常的食物摄入量，并且当祖先暴露于BPA时不会变得肥胖。结果表明，Fto的表观遗传改变可以导致与遗传变体相同的表型。
Exposure of pregnant female mice to bisphenol A (BPA) results in obesity in the F2 progeny, which can be transmitted in the absence of additional exposure up to the F6 generation. Obesity results from increased food consumption and its transmission correlates with the presence of a chromatin accessible site in a cis-regulatory element (CRE) present in an intron of the Fto gene, which becomes demethylated after BPA exposure. This CRE interacts with the Irx3 and Irx5 genes, which are involved in the differentiation of appetite-controlling neurons in the hypothalamus. Mice carrying a deletion of the CTCF site fail to become obese after exposure to BPA, suggesting that epigenetic changes in a CTCF site are responsible for transgenerational inheritance of obesity. The mechanisms by which environmentally-induced epiphenotypes are transmitted transgenerationally in mammals are poorly understood. Here we show that exposure of pregnant mouse females to bisphenol A (BPA) results in obesity in the F2 progeny due to increased food intake. This epiphenotype can be transmitted up to the F6 generation. Analysis of chromatin accessibility in sperm of the F1–F6 generations reveals alterations at sites containing binding motifs for CCCTC-binding factor (CTCF) at two cis-regulatory elements (CREs) of the Fto gene that correlate with transmission of obesity. These CREs show increased interactions in sperm of obese mice with the Irx3 and Irx5 genes, which are involved in the differentiation of appetite-controlling neurons. Deletion of the CTCF site in Fto results in mice that have normal food intake and fail to become obese when ancestrally exposed to BPA. The results suggest that epigenetic alterations of Fto can lead to the same phenotypes as genetic variants.
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