TE-associated chromatin variation in mice livers. Mus musculus

Chromatin accessibility is a hallmark of active regulatory function in the genome and variation of chromatin accessibility across individuals has been shown to contribute to complex traits and disease susceptibility. However, the mechanisms responsible for chromatin variation among different individuals and how this variation contributes to phenotypic diversity remain poorly understood. We examined chromatin accessibility variation in liver tissue from seven strains of adult mice that have phenotypic diversity in response to a high-fat/high-sucrose diet. Remarkably, nearly 40% of the loci with the greatest degree of chromatin variability across the strains are associated with transposable elements (TEs), with evolutionarily younger TEs being particularly enriched for regions of chromatin variation. We found that evolutionary younger and older TEs have differential chromatin accessibility profiles and are enriched for binding sites of different transcription factors, indicating the role of TEs in the evolution of regulatory networks in the liver. We also demonstrate that TE polymorphisms and epigenetic regulation of TEs contribute to regulatory variation across different strains through providing binding sites for liver transcription factors. Intriguingly, variable chromatin loci that are associated with liver metabolism are primarily TE-associated. We demonstrate that TEs contribute to regulatory variation in liver and have downstream effects on metabolism. Our data reveal TEs as a novel and important contributor to regulatory and phenotypic variation in the liver and suggest that regulatory variation at TEs is a major contributor to phenotypic variation in populations. Overall design: Examination of chromatin accessibility with FAIRE-seq in livers of male mice (A/J, AKR/J, BALB/cJ, C57BL/6J, C3H/HeJ, CBA/J, DBA/2J, BXH2/TyJ, and BXH19/TyJ) fed a high-fat, high-sucrose diet.

染色质开放性（chromatin accessibility）是基因组中活跃调控功能的标志性特征，个体间染色质开放性的变异已被证实与复杂性状及疾病易感性密切相关。然而，不同个体间染色质变异的潜在作用机制，以及该变异如何推动表型多样性的过程，目前仍有待深入阐释。
本研究针对7株成年小鼠的肝脏组织中的染色质开放性变异展开检测，这些小鼠在高脂高蔗糖饮食干预下呈现出显著的表型多样性。
值得注意的是，在各品系间染色质变异程度最高的基因座中，近40%与转座因子（transposable elements, TEs）相关，其中进化年代较新的转座因子在染色质变异区域的富集程度尤为突出。
研究发现，进化新旧程度不同的转座因子具有差异化的染色质开放性特征，且分别富集于不同转录因子的结合位点，这表明转座因子在肝脏调控网络的进化过程中发挥了关键作用。
本研究同时证实，转座因子的多态性及其表观遗传调控可通过为肝脏转录因子提供结合位点，推动不同品系间的调控变异。
有趣的是，与肝脏代谢相关的染色质可变基因座，主要均与转座因子相关。
本研究证实，转座因子可推动肝脏的调控变异，并对代谢产生下游效应。
本研究数据揭示，转座因子是肝脏调控与表型变异的一种全新且重要的驱动因素，并表明转座因子上的调控变异是种群内表型变异的主要贡献来源之一。
实验设计概述：采用甲醛辅助分离调控元件测序（FAIRE-seq）技术，对饲喂高脂高蔗糖饲料的雄性小鼠（品系包括A/J、AKR/J、BALB/cJ、C57BL/6J、C3H/HeJ、CBA/J、DBA/2J、BXH2/TyJ及BXH19/TyJ）的肝脏组织进行染色质开放性检测。