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

The escalating prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly linked to rising obesity rates. Maternal obesity (MO) increases offspring susceptibility to metabolic disorders, including MASLD. This elevated risk could be a consequence of epigenetic modifications established during fetal development, a period highly sensitive to the maternal diet. H3K9me3, a heterochromatin hallmark, silences gene programs dispensable for differentiated cell types. This study investigated how MO influences sex-specific gene expression and chromatin architecture in offspring liver. Female mice consumed a Western-style or control diet pre-pregnancy and throughout gestation/lactation. Offspring were weaned at 3 weeks and transitioned to chow for five weeks. At 3 weeks, liver transcriptomes of control offspring were similar between sexes. However, MO significantly disrupted hepatic gene expression in both sexes, dysregulating hundreds of genes and altering H3K9me3 binding. By 8 weeks, with sexual maturity, control offspring showed substantial sex-based gene expression divergence, predominantly genes involved in immune response, cell adhesion, xenobiotic detoxification, cholesterol metabolism, and lipid partitioning. Thousands of differentially bound H3K9me3 peaks were also observed between 3 and 8 weeks, with many on the female X chromosome. Remarkably, by 8 weeks, MO offspring showed incomplete normalization of gene expression, H3K9me3 profiles, and hepatic lipid classes, emphasizing the persistent impact of maternal diet on the genomic and metabolic landscape. This study highlights inherent sex differences in liver gene expression and suggests H3K9me3's role in establishing sex-specific liver function during sexual maturation. Moreover, MO disrupts these patterns, which are not fully corrected by postnatal dietary normalization.