The role of H3K4 demethylases in alcohol-associated liver disease development and resolution

PROJECT SUMMARY Alcohol-associated liver disease (ALD) is a major cause of alcohol related mortality. The specific mechanisms responsible for ALD development and progression are not fully understood, and there is limited therapy for any stage of ALD. Recent advances in single cell sequencing revealed the complex nature of the disease, particularly the importance of cell-cell communication. Using single cell sequencing and co-culture experiments we found that alcohol promotes pathological changes in cell-cell communication in the liver. These changes are in turn mediated by alcohol-related epigenetic changes in hepatocytes, induced by histone modification enzymes called KDM5B and KDM5C. Preliminary data suggest that KDM5 demethylases are involved in both ALD development and resolution. During disease development KDM5 demethylases in hepatocytes promote pro-inflammatory and pro-fibrotic signaling in non-parenchymal cells (NPC). During disease resolution KDM5 demethylases control hepatocyte-NPC crosstalk that suppresses pro-resolving macrophages and contributes to poor fibrosis resolution. Our data suggest that these diverse functions of KDM5 demethylases are mediated by set of transcription factors that control KDM5 expression or/and activity (chromatin binding) in hepatocytes. Some of these factors, such as C/EBPβ, STAT5B and Androgen receptor (AR) are sex-specific, and are involved in sex-specific alcohol response, while others such as LXR are sex-independent. Taken together our data suggest that hepatocyte KDM5 demethylases alter cellular crosstalk that promotes fibrosis development and contribute to poor fibrosis resolution after alcohol cessation. We propose to investigate the sex-specific and sex-independent roles of KDM5B and KDM5C in cell-cell communication in ALD with three specific aims: Aim 1 To determine the role of KDM5B and KDM5C in cellular crosstalk in ALD Aim 2 To define the mechanism of alcohol induced KDM5B and KDM5C activation in hepatocytes Aim 3 To study the role of KDM5B and KDM5C-mediated regulation in fibrosis resolution Results of the proposed project will provide novel insights into the nature of progression and resolution of alcohol-associated liver disease. It should determine the role of KDM5 demethylases in the alcohol response and identify the primary targets in males and females. The project will set the stage for further studies to understand the role of cellular communication in liver disease progression and explore the potential targets for therapy.