Identification of Key Regulators Associated with Diabetic Kidney Disease and COVID-19 Severity through Multi-omics Profiling

Abstract

Disease initiation and progression, and cell type-specific functions are regulated by diverse biological processes. In particular, the epigenome dynamically modulates gene expression through multiple layers, including chromatin architecture, chromatin accessibility, and histone modifications. These epigenetic changes are reversible yet durable and stable, providing crucial insights into disease-specific gene regulatory networks and key regulatory factors. Therefore, a comprehensive multi-omics approach is essential for understanding the epigenetic mechanisms underlying disease. In this study, I performed integrative multi-omics analyses of diabetic kidney disease (DKD) and COVID-19 severity, leveraging Hi-C and single-nucleus ATAC-seq, and single-cell multiome data. DKD and COVID-19 are complex disorders associated with distinct cellular and epigenetic alterations. Here, I employed a comprehensive single-cell multi-omics approach integrating transcriptomic profiling, chromatin accessibility (snATAC-seq), and three-dimensional chromatin architecture (Hi-C) to dissect disease-associated regulatory programs at high resolution. In DKD, genome-wide Hi-C analysis revealed dynamic changes in chromatin compartments and validated cell type-specific chromatin loops overlapping with cis-coaccessibility networks. Genes relocated to transcriptionally active compartments were enriched in inflammatory and NF-κB/TNF pathways. Proximal tubule cells exhibited an increased proportion of VCAM1+ subpopulations, indicative of kidney injury. Integrative analysis identified BACH1 as a central transcriptional regulator, with target genes such as ATP9A, C1QTNF1, and CXCL8 displaying increased chromatin accessibility and enhancer-promoter interactions. Functional perturbation confirmed BACH1-mediated regulation and revealed potential therapeutic relevance through modulation of oxidative stress and extracellular vesicle secretion. In parallel, I investigated immune cell heterogeneity underlying COVID-19 severity. Classical monocytes (cMono) were sub-clustered into four distinct subtypes with transcriptionally and epigenetically distinct programs. IL7R+ cMono exhibited hypo-inflammatory, T cell-like signaling mediated by ETS1, Wnt pathways, and TGF-β secretion, potentially mitigating excessive inflammation but promoting fibrosis. CD163+ cMono displayed an M2-like, pro-fibrotic phenotype with TGF-β/SMAD3 activation and JDP2-mediated AP-1 suppression, contributing to impaired antiviral responses and fibrosis. These subtype-specific regulatory programs correlate with disease severity and may persist via hematopoietic stem and progenitor cell imprinting. Collectively, my study highlights the critical roles of three-dimensional chromatin architecture and cell type-specific epigenetic regulation in DKD and COVID-19 pathogenesis. Identification of BACH1, ETS1, and JDP2 as central regulators provides mechanistic insights and potential therapeutic targets, and the generated single-cell multi-omics resource offers a foundation for future disease modeling and intervention strategies.