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

Little is known about how sex and diet interact at the level of chromatin organization. A comprehensive analysis of diet-induced chromatin dynamics can reveal how the liver mounts a rapid adaptive response to environmental cues and uncover mechanisms underlying sex differences. Here, we employed an integrative strategy to construct a nucleosome accessibility atlas of the mouse liver under different dietary conditions. Stringent analysis revealed a largely preserved hepatic chromatin landscape across feeding states, with sex being the critical factor driving changes in chromatin accessibility. Notably, lipid-rich diet preferentially enriched CCAAT-binding motifs in females, while nutrient-sensing nuclear receptor motifs were more strongly enriched in males. Furthermore, using the Four Core Genotypes model (XX ovaries / XY testes / XX testes / XY ovaries), we disentangled the effects of gonadal and chromosomal sex on diet-induced gene regulation. By leveraging this framework with multiple mouse models and molecular approaches, we identified a suppressive role of testosterone in regulating the sex-dimorphic GWAS gene PNPLA3. Overall, we establish an unbiased transcriptomic resource that revealed chromatin dynamics and identified gene clusters associated with distinct sex-related factors.