Identification of Foxm1 as a critical regulator for metabolic dysfunction-associated steatotic liver disease by epigenomic and transcriptional profiling

Epigenetic regulation has emerged as a key mechanism in metabolic dysfunction-associated steatotic liver disease (MASLD). However, the systematic epigenomic profiling for MASLD progression is still lacking. To investigate the epigenetic mechanisms regulating MASLD, this study performed chromatin immunoprecipitation sequencing (ChIP-Seq) for H3K27ac, H3K4me1, H3K4me3, H3K9me3, and H3K27me3, along with transcriptomic profiling, using liver tissues from multiple stages of a Gubra-Amylin NASH (GAN) diet-induced mouse model. Transcriptomic analysis defined the 8- and 16-week time points as the inflammation stage, and the 20- and 24-week as the fibrosis stage. Chromatin state analysis revealed that enhancer and polycomb regions increase during MASLD progression. Differential enhancers were defined based on H3K27ac peaks, and Foxm1 was identified as a key transcription factor involved in MASLD. In vitro and in vivo experiments demonstrate that lipid droplets accumulate in Foxm1 -knockdown liver cells. Further studies indicate Foxm1 represses MASLD progression by regulating key genes involved in lipid storage and cholesterol homeostasis. Taken together, our work has provided important datasets and identified Foxm1 as a repressive transcription factor for MASLD progression. • The temporal epigenomic dynamics is profiled in the GAN-diet MASLD model. • Enhancer and polycomb regions increase during MASLD progression. • Foxm1 is a key transcription factor in MASLD, whose protein level decreases along with disease progression. • Foxm1 represses MASLD by regulating key genes involved in lipid storage and cholesterol homeostasis.