Epigenetic Modifications in the Murine Liver upon Depletion of Transcriptional Coregulator Host Cell Factor 1

Background: Dynamic regulation of gene expression is essential for the proper functioning of any biological system. Transcriptional co-regulators play an important role in orchestrating gene transcription by modulating the activity of transcription factors and chromatin remodelling complexes. One such evolutionarily conserved metazoan transcriptional co-regulator is HCF-1. Recently, apart from cell cycle progression, HCF-1 has also been implicated in development, liver regeneration, and metabolism. Loss of HCF-1 in murine livers leads to spontaneous development of NAFLD that eventually exacerbates to NASH. Deletion of hepatocyte-specific expression of HCF-1 also impairs the regenerative abilities of murine liver when subjected to surgical resection. While its role in transcriptional regulation is well-established, the impact of HCF-1 on epigenetic modifications remains relatively unexplored. Methods: Here, we aim to elucidate the epigenetic changes occurring in the murine liver upon hepatocyte specific loss of HCF-1. To identify the epigenetic changes in the murine liver upon loss of HCF-1, we performed chromatin immunoprecipitation followed by high throughput sequencing for trimethylated H3K4 and RNA polymerase II , presence of which is indicative of active gene transcription. By analysing the ChIP-Seq data, we dissect affected cellular pathways due to induced HCF-1 loss and aim to understand its impact on hepatic function. Results: Upon loss of HCF-1, we observe differential histone modification patterns at enhancer and promoter regions of genes associated with metabolic pathways, cell cycle regulation, and liver function. Furthermore, integrative analyses of gene expression data in conjunction with epigenetic profiles provide insights into potential mechanisms underlying HCF-1-mediated hepatic regulation. Conclusions: Our study underscores the significance of HCF-1 as a critical player in maintaining hepatic epigenomic integrity and highlights its role in modulating gene regulatory networks through epigenetic modifications. Keywords: HCF-1, epigenetics, methylation, ChIP-seq, non-alcoholic fatty liver disease