Genetic factors contributing to extensive variability of sex-specific hepatic gene expression in Diversity Outbred mice

Abstract

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.

The Relationship between Long Noncoding RNA H19 Polymorphism and the Epidermal Growth Factor Receptor Phenotypes on the Clinicopathological Characteristics of Lung Adenocarcinoma

“…In the gender subgroup analysis of the current study, the female EGFR mutation population showed a higher distribution frequency of LncRNA H19 SNP rs217727 as well as rs2107425 but a lower distribution frequency of LncRNA H19 SNP rs2839698. The difference of LncRNA H19 SNP distribution between the two gender subgroups may be due to the existence of expression quantitative trait loci which lead to gender-difference expression of LncRNA inter chr4 3011 in mice [ 46 ] and the possible difference function of EGFR pathway between gender, which is found in the kidney mouse [ 47 ], may also cause such gender difference as the expression of LncRNA PACER in periodontitis [ 48 ]. Since the LncRNA H19 SNP rs217727 was related to lung cancer development [ 45 ] and LncRNA H19 SNP rs2107425 was correlated to shorter metastasis-free survival [ 49 ], it may be reasonable for the similar condition in the current study.…”

Harnessing natural variation to identify cis regulators of sex-biased gene expression in a multi-strain mouse liver model

“…We describe the genetic effects uncovered by eQTL analysis in DO mice in relation to the regulating founder strain as was described previously [49]. For instance, if eQTL analysis in male DO mice yields an eQTL with a negative regression coefficient, and with CAST as the regulating strain, the gene target of this eQTL is referred to as repressed in CAST male liver.…”

“…Of the eQTLs regulating sexbiased genes in liver with CAST or B6 as the regulating strain, 355 eQTLs are associated with genes that are significantly sex-biased in B6 and/or CAST mouse liver and 388 eQTLs can be categorized into one of 8 categories described below (Table S6A, column X; Table S6G). The number of eQTLs that can be categorized (388 of 491) is less than 491 because we only considered eQTLs that are significant in the DO mouse male-only liver set (n=219), or in the DO mouse female-only liver set (n=219), and for which CAST or B6 is the regulating strain, or contributes substantially to the regulation as indicated by a regression coefficient within 20% of the absolute maximum regression coefficient in the regulating strain, as determined in [49]. The intersection of the 355 eQTLs regulating genes showing sex-biased expression in either B6 and/or CAST livers with the 388 categorized eQTLs resulted in 286 eQTLs (Fig.…”

“…Analysis of such evolutionary changes at CREs between closely related species, or across strains within a species, provides an opportunity to discover functional roles of specific regulatory elements [44][45][46]. Genetic diversity across mouse strains and subspecies results in well-characterized phenotypic [47,48], transcriptomic [49][50][51], and epigenetic differences in the liver [44][45][46]. Furthermore, extensive transcriptomic and epigenetic studies on liver sex differences in the outbred mouse strain CD-1 have identified large numbers of GHregulated CREs that differ between the sexes [38,[52][53][54].…”

Global analysis of expression, maturation and subcellular localization of mouse liver transcriptome identifies novel sex-biased and TCPOBOP-responsive long non-coding RNAs

“…A few hundred liver-expressed lncRNA genes were shown to respond to pituitary growth hormone secretory patterns [ 23 ], a key factor regulating sex-biased gene expression in the liver [ 32 – 34 ]. Furthermore, sex and strain-dependent genetic regulation was characterized in livers of Diversity Outbred mice [ 35 ], where co-expression network analysis identified sex-biased lncRNAs likely to control sex-biased PCG expression through negative regulatory mechanisms [ 26 ]. Furthermore, liver lncRNAs that respond to xenobiotic exposure and may impact xenobiotic toxicity have been identified [ 22 , 36 – 39 ] and were closely linked to xenobiotic dysregulation of pathways involving fatty acid metabolism, cell division and immune responses [ 27 ].…”