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

## TL;DR

This study explores how sex and diet interact to influence gene regulation in the liver, revealing sex-specific chromatin and transcriptomic responses.

## Contribution

The study introduces an integrative approach to uncover sex-specific mechanisms of gene regulation in hepatic nutrient responses.

## Key findings

- Sex is the critical factor driving changes in chromatin accessibility in the liver.
- Lipid-rich diets enrich CCAAT-binding motifs in females and nuclear receptor motifs in males.
- Testosterone suppresses the regulation of the sex-dimorphic GWAS gene PNPLA3.

## Abstract

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.

Metabolic diseases, including fatty liver diseases, are often influenced by biological sex. This study provides a detailed characterization of how sex and diet interact to shape molecular responses in the mouse liver, teasing apart how gonadal and chromosomal sex influence diet-induced transcriptomic and chromatin dynamics.