Integrated chromatin and transcriptomic profiling reveals sex-specific mechanisms of gene regulation in hepatic nutrient responses

The three-dimensional organizing of the genome plays an important role in cellular function. Alterations between open and closed chromatin states contributes to DNA binding, collaborative transcriptional activities and informs post-transcriptional processing. The liver is the primary site orchestrating metabolic control, needing to mount a rapid adaptive response to environmental challenges. Here, we leveraged ATAC-seq to interrogate the chromatin architecture in liver under different dietary cues. We mapped over 120,000 nucleosome peaks, revealing a remarkably preserved hepatic chromatin landscape across feeding conditions. Stringent analysis of nucleosome rearrangements, unexpectedly, nominated sex as the most dominant factor segregating changes in chromatin accessibility. Lipid-rich diet led to a more accessible chromatin confirmation at promoter regions in female mice along with enrichment of promoter binding CCAAT-binding domain proteins. Male liver exhibited stronger binding for nutrient sensing nuclear receptors. Integrative analysis with gene expression and lipid composition corroborates a role for chromatin states in informing functional differences in metabolic traits. We uncouple the influence of gonadal and sex-chromosomal factors using the Four Core Genotype mouse model. Leveraging our framework, we provide mechanistic evidence underlying the regulation for the critical sex-dimorphic GWAS gene, Pnpla3. In summary, we provide a comprehensive epigenetic resource in murine liver that uncovers the complexity of chromatin dynamics in response to diet and sex.