Identification of IL-34 and Slc7al as potential key regulators in MASLD progression through epigenomic profiling.

OBJECTIVE: Epigenetic alterations are critical regulators in the progression of metabolic dysfunction-associated steatotic liver disease (MASLD); however, the dynamic epigenomic landscapes are not well defined. Our previous study found that H3K27ac and H3K9me3 play important roles in regulating lipid metabolic pathways in the early stages of MASLD. However, the epigenomic status in the inflammation stages still needs to be determined. METHOD: C57BL/6 male mice were fed with the methionine- and choline-deficient (MCD) or normal diet, and their serum and liver samples were collected after 6 weeks. Serum alanine aminotransferase (ALT), aspartate amino transferase (AST), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels were measured. Chromatin immunoprecipitation sequencing (ChIP-Seq) for H3K27ac and H3K9me3 was performed together with RNA sequencing (RNA-seq) and key regulators were analyzed. RESULTS: The target genes of enhancers with increased H3K27ac and decreased H3K9me3 signals are enriched in lipid metabolism and immuno-inflammatory pathways. Il-34 and Slc7al are identified as potential regulators in MASLD. CONCLUSION: Our study reveals that active enhancers and heterochromatin associated with metabolic and inflammatory genes are extensively reprogrammed in MCD-diet mice, and Il-34 and Slc7al are potentially key genes regulating the progression of MASLD.