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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE304113 | GEO | 2025/11/01

REPOSITORIES: GEO

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Project description:Maternal diet is associated with the development of metabolism-related and other non-communicable diseases in offspring. Underlying mechanisms, functional profiles, and molecular markers are only starting to be revealed. Here, we explored the physiological and molecular impact of maternal Western-style diet on the liver of male and female offspring. C57BL/6 dams were exposed to either a low fat/low cholesterol diet (LFD) or a Western-style high fat/high cholesterol diet (WSD) for six weeks before mating, as well as during gestation and lactation. Dams and offspring were sacrificed at postnatal day 14, and body, liver, and blood parameters were assessed. The impact of maternal WSD on the pups' liver gene expression was characterised by whole-transcriptome microarray analysis. Exclusively male offspring had significantly higher body weight upon maternal WSD. In offspring of both sexes of WSD dams, liver and blood parameters, as well as hepatic gene expression profiles were changed. In total, 686 and 604 genes were differentially expressed in liver (pM-bM-^IM-$0.01) of males and females, respectively. Only 10% of these significantly changed genes overlapped in both sexes. In males, in particular alterations of gene expression with respect to developmental functions and processes were observed, such as Wnt/beta-catenin signalling. In females, mainly genes important for lipid metabolism, including cholesterol synthesis, were changed. We conclude that maternal WSD affects physiological parameters and induces substantial changes in the molecular profile of the liver in two-week-old pups. Remarkably, the observed biological responses of the offspring reveal pronounced sex-specificity. C57BL/6 dams were exposed to either a low fat/low cholesterol diet (LFD) or a Western-style high fat/high cholesterol diet (WSD) as six weeks pre-treatment before mating, as well as during gestation and lactation. Offspring were sacrificed at postnatal week two, livers were removed and RNA samples were subjected to gene expression profiling.

Project description:Maternal high-fat diet consumption predisposes to metabolic and liver dysfunction in F1 male and female at young adulthood. Purpose: We used RNA-seq to determine the liver transcriptome of male and female F1 of MO and control fed mothers. Methods: Female Wistar rat mothers ate control (C) or obesogenic (MO) diet from the time they were weaned through breeding at postnatal day (PND) 120, delivery and lactation. After weaning all male and female F1 ate control diet. At PND 110 liver and fat were collected to analyze metabolites, histology and liver differentially expressed genes. To identify the functional F1 liver changes due to MO, we evaluated the differentially expressed genes (DEGs) between MO and C males and females with separate pairwise comparisons due to the marked differences between males and females. Genes were filtered based on ≥ 1.4 fold change (FC) and nominal P value <0.05 (Student´s t-test). Results: MOF1 males presented greater physiologic and histological NAFLD characteristics than MOF1 females. RNA-seq revealed 1,365 genes significantly changed in male MOF1 liver and only 70 genes in MOF1 female compared with controls. GO and KEGG analysis identified differentially expressed genes related to metabolic process. Male MOF1 liver showed the following altered pathways: insulin signaling (22 genes), phospholipase D signaling (14 genes), NAFLD (13 genes), and glycolysis/ gluconeogenesis (7 genes). In contrast, few genes were altered in these pathways in MOF1 females. Conclusions: These results improve understanding of the mechanism by which a maternal high fat diet affects their F1. In summary, MO programs sex-dependent F1 changes in insulin, glucose and lipid signaling pathways, leading to liver dysfunction and insulin resistance. Male adult MOF1 livers show global down-regulation of genes that are required for normal function of major liver metabolic pathways. This new knowledge is important for producing sex-specific interventions.

Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease, has emerged as the most common chronic liver disease globally, affecting more than one-third of the world’s population. Its rate has increased by 13%, rising from 25% to 38% over the past three decades. MASLD is characterized by excessive fat accumulation in hepatocytes and, if left untreated, progresses to its more severe form, metabolic dysfunction-associated steatohepatitis (MASH), which poses a significant global health concern as one of the leading causes of cirrhosis, cirrhotic complications, and hepatocellular carcinoma. The molecular determinants of MASLD stratification are not clearly defined and require additional investigation. In this study, we used male and female CC042 mice, a Collaborative Cross mouse strain susceptible to the development of MASLD, to analyze the global transcriptomic profile in liver and to clarify the molecular mechanisms involved in the progression of the disease. Male and female CC042 mice were maintained on a high fat/high sucrose (HF/HS) diet for 20, 40, or 60 weeks, and hepatic gene expression profiles were determined by next-generation RNA sequencing. Chronic feeding of the HF/HS diet induced profound alterations in gene expression at all time points. The number of significantly differentially expressed genes (DEGs) in the livers of male mice was greater than female mice at 20 and 40 weeks and reached a maximum of 2764 genes at 40 weeks. In contrast, the number of DEGs in the livers of female mice steadily increased with the time on diet reaching a maximum of 2974 DEGs at 60 weeks after HF/HS diet initiation. The number of upregulated DEGs was higher than downregulated DEGs in both male and female mice at all time points. Functional analysis of DEGs showed that in both sexes, the most dysregulated liver toxicity-related pathways were associated with liver fibrosis, liver necrosis/cell death, inflammation, steatosis, liver damage, and liver proliferation/hyperplasia. In male mice, pathways associated with fibrosis, necrosis/cell death, inflammation, and steatosis remained constant from 20 to 40 weeks, and activation of liver hyperplasia pathway was constant from 40 and 60 weeks. In contrast, in female mice, dysregulation of genes associated with these pathways gradually increased from 20 to 60 weeks after HF/HS diet initiation. Importantly, we found that the expression of 701 and 871 genes significantly correlated with total NASH pathology scores (Pearson r > |0.8|) in the livers of male and female mice, respectively. These findings provide comprehensive insights into the dynamics of time- and sex-specific transcriptomic changes during NAFLD progression. This knowledge can be helpful for identifying promising targets for prevention and treatment, as well as for determining key potential biomarkers of NAFLD to NASH progression.

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

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