Abstract
Sex-differences in human liver gene expression were characterized on a genome-wide scale using a large liver sample collection, allowing for detection of small expression differences with high statistical power. 1,249 sex-biased genes were identified, 70% showing higher expression in females. Chromosomal bias was apparent, with female-biased genes enriched on chrX and male-biased genes enriched on chrY and chr19, where 11 male-biased zinc-finger KRAB-repressor domain genes are distributed in six clusters. Top biological functions and diseases significantly enriched in sex-biased genes include transcription, chromatin organization and modification, sexual reproduction, lipid metabolism and cardiovascular disease. Notably, sex-biased genes are enriched at loci associated with polygenic dyslipidemia and coronary artery disease in genome-wide association studies. Moreover, of the 8 sex-biased genes at these loci, 4 have been directly linked to monogenic disorders of lipid metabolism and show an expression profile in females (elevated expression of ABCA1, APOA5 and LDLR; reduced expression of LIPC) that is consistent with the lower female risk of coronary artery disease. Female-biased expression was also observed for CYP7A1, which is activated by drugs used to treat hypercholesterolemia. Several sex-biased drug-metabolizing enzyme genes were identified, including members of the CYP, UGT, GPX and ALDH families. Half of 879 mouse orthologs, including many genes of lipid metabolism and homeostasis, show growth hormone-regulated sex-biased expression in mouse liver, suggesting growth hormone might play a similar regulatory role in human liver. Finally, the evolutionary rate of protein coding regions for human-mouse orthologs, revealed by dN/dS ratio, is significantly higher for genes showing the same sex-bias in both species than for non-sex-biased genes. These findings establish that human hepatic sex differences are widespread and affect diverse cell metabolic processes, and may help explain sex differences in lipid profiles associated with sex differential risk of coronary artery disease.
Highlights
Mammalian sex determination is initiated by the SRY gene, which activates a developmental pathway leading to testis formation and establishes life-long sex differences in the patterns of gonadal hormone secretion [1]
We report that sex-biased gene expression is most significantly associated with genes that participate in or regulate lipid metabolism, several of which have previously been associated with polygenic dyslipidemia and cardiovascular disease in genome wide association studies (GWAS) analyses or are established drug targets for treatment of hyperlipidemia and hypercholesterolemia
Genes showing sex-biased expression in human liver Human liver RNA was isolated from 112 male and 112 female livers, from which 16 male liver RNA pools and 16 female liver RNA pools were prepared and analyzed on two-color microarrays. 1,249 genes showing sex differences in expression were identified based on a combination of three criteria: mean |fold change| between male and female liver .1.15, p-value,0.005, and composite array score $14, with an apparent false discovery rate (FDR),1%. 873 of the 1,249 genes (70%) were expressed at a higher level in female liver and 376 genes (30%) were expressed at a higher level in male liver (Table S2A)
Summary
Mammalian sex determination is initiated by the SRY gene, which activates a developmental pathway leading to testis formation and establishes life-long sex differences in the patterns of gonadal hormone secretion [1]. In turn, exert permanent differentiating effects (‘organizational’ actions) as well as short-term stimulatory effects that lead to sex differences in gene expression in multiple tissues [2]. Sex differences are induced by non-gonadal signals and factors, including direct sexbiased effects of individual X and Y-chromosome genes [3]. Sex differences characterize histone acetylation and histone methylation [10] and the expression of certain histone demethylases [11,12]. Sexual differentiation is achieved through a complex interplay of multiple mechanisms [13]
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