Genetic factors contributing to extensive variability of sex-specific hepatic gene expression in Diversity Outbred mice.
Genetic factors contributing to extensive variability of sex-specific hepatic gene expression in Diversity Outbred mice.
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遗传因素有助于多样性刺激小鼠中性别特异性肝基因表达的广泛差异。
DOI：
10.1371/journal.pone.0242665
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发表时间：
2020
期刊：
影响因子：
3.7
通讯作者：
Waxman DJ
中科院分区：
文献类型：
--
作者：
Melia T;Waxman DJ
小鼠肝脏中的数百个基因具有性别特异性转录特征，其中许多基因与性别差异、药物和脂肪代谢以及疾病易感性有关。虽然生长激素激活的STAT5对肝脏性别差异的调节是众所周知的，但对常染色体遗传因素调节性别特异的肝脏转录组却知之甚少。在这里，我们使用来自大量多样性近交系小鼠的基因分型和表达数据表明，遗传因素与生长激素协同作用，控制数百个性别偏见基因的个体变异性，包括许多长的非编码RNA基因。单核苷酸多态与性别特异性基因表达之间的显著关联被鉴定为表达数量性状基因座(EQTL)，其中许多eQTL显示出强烈的性别相关性。值得注意的是，性别特异基因的常染色体遗传修饰物被发现在八个不同的近交系小鼠创始人品系中解释了200多例性别特异性的获得或丧失。性别偏向的STAT5结合位点和带有菌株特异性变体的开放染色质区域在调节相应性别特异基因的eQTL区域显著丰富，支持所确定的eQTL区域的功能调节性质。雄性偏向的生长激素调节的抑制物BCL6的结合在控制雌性特有基因的跨eQTL区域高度丰富。由重叠的eQTL定义的共同调控的基因簇包括来自不同染色体的高度相关的基因集，进一步支持跨eQTL的作用。这些发现阐明了出人意料的大量常染色体因素如何与生长激素信号通路协同工作，以调节与肝脏代谢和疾病中的性别差异相关的个体变异性。
Sex-specific transcription characterizes hundreds of genes in mouse liver, many implicated in sex-differential drug and lipid metabolism and disease susceptibility. While the regulation of liver sex differences by growth hormone-activated STAT5 is well established, little is known about autosomal genetic factors regulating the sex-specific liver transcriptome. Here we show, using genotyping and expression data from a large population of Diversity Outbred mice, that genetic factors work in tandem with growth hormone to control the individual variability of hundreds of sex-biased genes, including many long non-coding RNA genes. Significant associations between single nucleotide polymorphisms and sex-specific gene expression were identified as expression quantitative trait loci (eQTLs), many of which showed strong sex-dependent associations. Remarkably, autosomal genetic modifiers of sex-specific genes were found to account for more than 200 instances of gain or loss of sex-specificity across eight Diversity Outbred mouse founder strains. Sex-biased STAT5 binding sites and open chromatin regions with strain-specific variants were significantly enriched at eQTL regions regulating correspondingly sex-specific genes, supporting the proposed functional regulatory nature of the eQTL regions identified. Binding of the male-biased, growth hormone-regulated repressor BCL6 was most highly enriched at trans-eQTL regions controlling female-specific genes. Co-regulated gene clusters defined by overlapping eQTLs included sets of highly correlated genes from different chromosomes, further supporting trans-eQTL action. These findings elucidate how an unexpectedly large number of autosomal factors work in tandem with growth hormone signaling pathways to regulate the individual variability associated with sex differences in liver metabolism and disease.
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影响因子：
2.5
作者：
Churchill, Gary A.;Gatti, Daniel M.;Munger, Steven C.;Svenson, Karen L.
通讯作者：
Svenson, Karen L.
影响因子：
4.8
作者：
Connerney, Jeannette;Lau-Corona, Dana;Waxman, David J.
通讯作者：
Waxman, David J.
DOI：
10.1210/jc.2018-00423
发表时间：
2018-12-01
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
--
作者：
García-Calzón S;Perfilyev A;de Mello VD;Pihlajamäki J;Ling C
通讯作者：
Ling C
影响因子：
--
作者：
Conforto, Tara L.;Steinhardt, George F.;Waxman, David J.
通讯作者：
Waxman, David J.
影响因子：
4.2
作者：
Dai, Dongling;Mills, Philippa B.;Clayton, Peter T.
通讯作者：
Clayton, Peter T.