Genome Restructuring around Innate Immune Genes in Monocytes in Alcohol-associated Hepatitis

Abstract

Many inflammatory genes in the immune system are clustered in the genome. The 3D genome architecture of these clustered genes likely plays a critical role in their regulation and alterations to this structure may contribute to diseases where inflammation is poorly controlled. Alcohol-associated hepatitis (AH) is a severe inflammatory disease that contributes significantly to morbidity in alcohol associated liver disease. Monocytes in AH are hyper-responsive to inflammatory stimuli and contribute significantly to inflammation. We performed high throughput chromatin conformation capture (Hi-C) technology on monocytes isolated from 4 AH patients and 4 healthy controls to better understand how genome structure is altered in AH. Most chromosomes from AH and healthy controls were significantly dissimilar from each other. Comparing AH to HC, many regions of the genome contained significant changes in contact frequency. While there were alterations throughout the genome, there were a number of hotspots containing a higher density of changes in structure. A few of these hotspots contained genes involved in innate immunity including the NK-gene receptor complex and the CXC-chemokines. Finally, we compare these results to scRNA-seq data from patients with AH challenged with LPS to predict how chromatin conformation impacts transcription of clustered immune genes. Together, these results reveal changes in the chromatin structure of monocytes from AH patients that perturb expression of highly clustered proinflammatory genes.