Harnessing natural variation to identify cis regulators of sex-biased gene expression in a multi-strain mouse liver model.
Harnessing natural variation to identify cis regulators of sex-biased gene expression in a multi-strain mouse liver model.
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DOI：
10.1371/journal.pgen.1009588
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发表时间：
2021-11
期刊：
影响因子：
4.5
通讯作者：
Waxman DJ
中科院分区：
文献类型：
--
作者：
Matthews BJ;Melia T;Waxman DJ
基因表达的性别差异在肝脏中广泛存在，其中许多常染色体因子与生长激素信号传导协同作用，调节肝脏代谢和疾病中性别差异的个体变异性。在这里，我们比较了小鼠品系C57BL/6J和CAST/EiJ的肝脏转录组学和表观遗传学特征，代表了两个由50 - 100万年进化分离的亚种，以阐明调节肝脏性别差异的遗传因素的作用。我们确定了144个蛋白质编码基因和78个lncRNA显示菌株保守的性别偏见;许多具有与肝功能相关的基因本体，具有更高的肝脏特异性，显示出更大的性别偏见，并且比性别偏见依赖于菌株的基因更接近调节。菌株保守的基因包括关键的生长依赖性转录调控肝脏性别偏见，然而，其他三个转录因子，Trim24，Tox，和Zfp809，失去其性别偏见的表达在CAST/EiJ小鼠肝脏。为了阐明所观察到的应变的表达特异性，我们的特点是应变依赖性的性别偏见的染色质开放和增强子标记在顺式调控元件（CREs）内的表达数量性状基因座（eQTL）调节肝脏性别偏见的基因。引人注目的是，208的286个eQTL与株系特异性，性别差异的影响表达与一个完整的增益，损失，或逆转株系之间的性别差异表达。此外，286个eQTL中有166个与性别偏向的CRE的株系依赖性增加或损失相关。值得注意的是，这些CREs的一个子集显然缺乏菌株特异性遗传变异，但显示出协调的，菌株依赖性性别偏见的表观遗传调控。因此，我们直接将数百种菌株特异性遗传变异与CRE活性和性别偏见基因表达的高变异性联系起来，并揭示了遗传多样性小鼠群体中控制肝脏性别偏见的潜在遗传决定的表观遗传状态。肝脏基因表达的男女差异赋予了与人类健康和疾病相关的各种生物学过程的性别差异，但由于其相同的遗传背景，很难在近交系小鼠中建模。远交系小鼠提供了一些变异性，但啮齿动物性别偏见的跨品系研究还没有得到很好的研究。在这里，我们阐明了遗传因素调节肝脏性别差异的两个多样性远交小鼠创始人小鼠品系，C57BL/6和CAST/EiJ的行动。我们发现，许多菌株的性别偏向基因表达的差异可以链接到一个或多个菌株特异性序列变异相关的顺式调控元件的增益或损失。引人注目的是，在许多情况下，相关的顺式调控元件缺乏菌株特异性变体，但受到协调，应变依赖性表观遗传调控。因此，利用自然发生的遗传多样性远交小鼠的力量，我们整合了遗传，表观遗传和转录组水平上的生物学数据，跨越进化上不同的小鼠品系，发现了数百个控制肝脏表型性别差异的局部基因组区域。这些发现可以作为研究人类遗传变异以及人群范围内的变异对健康和疾病性别差异的影响的模型。
Sex differences in gene expression are widespread in the liver, where many autosomal factors act in tandem with growth hormone signaling to regulate individual variability of sex differences in liver metabolism and disease. Here, we compare hepatic transcriptomic and epigenetic profiles of mouse strains C57BL/6J and CAST/EiJ, representing two subspecies separated by 0.5–1 million years of evolution, to elucidate the actions of genetic factors regulating liver sex differences. We identify 144 protein coding genes and 78 lncRNAs showing strain-conserved sex bias; many have gene ontologies relevant to liver function, are more highly liver-specific and show greater sex bias, and are more proximally regulated than genes whose sex bias is strain-dependent. The strain-conserved genes include key growth hormone-dependent transcriptional regulators of liver sex bias; however, three other transcription factors, Trim24, Tox, and Zfp809, lose their sex-biased expression in CAST/EiJ mouse liver. To elucidate the observed strain specificities in expression, we characterized the strain-dependence of sex-biased chromatin opening and enhancer marks at cis regulatory elements (CREs) within expression quantitative trait loci (eQTL) regulating liver sex-biased genes. Strikingly, 208 of 286 eQTLs with strain-specific, sex-differential effects on expression were associated with a complete gain, loss, or reversal of the sex differences in expression between strains. Moreover, 166 of the 286 eQTLs were linked to the strain-dependent gain or loss of localized sex-biased CREs. Remarkably, a subset of these CREs apparently lacked strain-specific genetic variants yet showed coordinated, strain-dependent sex-biased epigenetic regulation. Thus, we directly link hundreds of strain-specific genetic variants to the high variability in CRE activity and expression of sex-biased genes and uncover underlying genetically-determined epigenetic states controlling liver sex bias in genetically diverse mouse populations. Male-female differences in liver gene expression confer sex differences in diverse biological processes relevant to human health and disease but are difficult to model in inbred mice given their identical genetic backgrounds. Outbred mice provide some variability, but cross-strain studies of sex bias in rodents have not been well studied. Here we elucidate the actions of genetic factors regulating liver sex differences in two Diversity Outbred mouse founder mouse strains, C57BL/6 and CAST/EiJ. We find that many of the strain differences in sex-biased gene expression can be linked to the gain or loss of a cis regulatory element associated with one or more strain-specific sequence variants. Strikingly, in many cases, the associated cis regulatory element lacked strain-specific variants, yet was subject to coordinated, strain-dependent epigenetic regulation. Thus, harnessing the power of naturally occurring genetic diversity of Diversity Outbred mice, we integrated biological data at the genetic, epigenetic, and transcriptomic levels across evolutionary divergent mouse strains to discover hundreds of localized genomic regions that control phenotypic sex differences in the liver. These findings may serve as a model for studies of human genetic variation and the effect of population-wide variation on sex differences in health and disease.
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