Sallam, T. | Search bioRxiv

bioRxiv2024

A genome-wide ATLAS of liver chromatin architecture reveals that sex dictates diet-induced nucleosome dynamics

The three-dimensional organization 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 orchestrates systemic metabolic control and has the ability to mount a rapid adaptive response to environmental challenges. We interrogated the chromatin architecture in liver under different dietary cues. Using ATAC-seq, we mapped over 120,000 nucleosome peaks, revealing a remarkably preserved hepatic chromatin landscape across feeding conditions. Stringent analysis of nucleosome rearrangements in response to diet revealed that sex is the dominant factor segregating changes in chromatin accessibility. A 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 corroborated a role for chromatin states in informing functional differences in metabolic traits. We distinguished the impact of gonadal sex and chromosomal sex as determinants of chromatin modulation by diet using the Four Core Genotypes mouse model. Our data 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. HighlightsATAC-Seq, RNA-Seq, and FCG model-integrated analysis unravel sex differences in chromatin accessibility and transcriptome responses to dietary challenges. Lipid-rich diet led to sex-biased chromatin confirmation at promoter regions. Gonadal sex emerged as the most prevalent determinant of the sex bias hepatic chromatin modulation by lipid-rich diets. The critical sex-dimorphic GWAS gene Pnpla3 is suppressed by testosterone, which underlies hepatic differences in expression between the sexes.

molecular biology↗

bioRxiv2024

Hepatic lipopolysaccharide binding protein partially uncouples inflammation from fibrosis in MAFLD

Non-alcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is the most common liver disease worldwide. The progression to fibrosis, occurring against a backdrop of hepatic steatosis and inflammation, critically determines liver-related morbidity and mortality. Inflammatory processes contribute to various stages of MAFLD and thought to instigate hepatic fibrosis. For this reason, targeting inflammation has been heavily nominated as a strategy to mitigate liver fibrosis. Lipopolysaccharide binding protein (LBP) is a secreted protein that plays an established role in innate immune responses. Here, using adoptive transfer studies and tissue-specific deletion models we show that hepatocytes are the dominant contributors to circulating LBP. In a murine model of MAFLD, hepatocyte-specific deletion of LBP restrained hepatic inflammation and improved liver function abnormalities, but not measures of fibrosis. Human studies, including genetic evidence, corroborate an important role for LBP in hepatic inflammation with minimal impact on fibrosis. Collectively, our data argues against the idea that targeting hepatic inflammation is a viable approach to reducing fibrosis.

physiology↗