Establishment of sex-specific liver transcriptomes and H3K9me3 profiles during sexual maturity: the impact of maternal obesity

Abstract

Background: The escalating prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to rising obesity rates. Maternal obesity (MO) is associated with increased susceptibility to metabolic disorders, including MASLD, in the offspring. This elevated risk could be a consequence of epigenetic modifications established during fetal development, a period highly sensitive to the maternal diet. H3K9me3, a hallmark of heterochromatin, plays a vital role in development by silencing gene programs dispensable for differentiated cell types. This study investigated how MO influences gene expression and chromatin architecture in male and female offspring liver, in early postnatal live and upon sexual maturity. Methods: Female mice were fed a Western-style diet or a control diet before and throughout pregnancy and lactation. The offspring were weaned at 3 weeks and subsequently transitioned to a standard chow diet for 5 weeks. Results: At 3 weeks, the liver transcriptomes of control offspring were similar between sexes. However, MO disrupted hepatic gene expression in both sexes, leading to the dysregulation of hundreds of genes and alterations in H3K9me3 binding patterns. By 8 weeks, as the mice reached sexual maturity, control offspring showed considerable sex-based gene expression divergence, with over 1,800 genes showing differential expression. These genes were predominantly involved in immune response regulation, cell adhesion and extracellular matrix organization, xenobiotic and glutathione-mediated detoxification, cholesterol metabolism, and lipid partitioning. Furthermore, thousands of differentially bound H3K9me3 peaks were observed between the 3- and 8-week time points. A significant fraction of these peaks were located on the X chromosome in females, suggesting a role in X inactivation. Remarkably, MO offspring displayed incomplete normalization of gene expression, H3K9me3 profiles, and hepatic lipid classes by week 8, underscoring the long-term impact of maternal diet on the genomic and metabolic landscape. Conclusions: Collectively, this study highlights inherent sex differences in liver gene expression, and suggests that H3K9me3 plays a role in establishing sex-specific liver function during sexual maturation. Moreover, MO disrupts these patterns, which are not fully corrected by 5 weeks of postnatal dietary normalization.