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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\n                    <jats:italic>PNPLA3<\/jats:italic>\n                    . Overall, we establish an unbiased transcriptomic resource that revealed chromatin dynamics and identified gene clusters associated with distinct sex-related factors.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3003601","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T18:37:46Z","timestamp":1770921466000},"page":"e3003601","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated chromatin and transcriptomic profiling reveals sex-specific mechanisms of gene regulation in hepatic nutrient 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