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Multimodal profiling of chromatin accessibility and gene expression in single cells enables the ...

Eunji Ha, PhD (1,2,3,4), Han Yuan, PhD (5), Amin Abedini, MD, PhD (1,2,3,4), Konstantin A. Kloetzer, MD (1,2,3,4), Andrea Sanchez Navarro, PhD (1,2,3), Daigoro Hirohama, MD, PhD (1,2,3), David Kelley, PhD (5), Katalin Susztak, MD, PhD (1,2,3,4) 1Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA 2Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA 3Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA 4Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA 5Calico Life Sciences, South San Francisco, CA 94080, USA


Poster # 26


Chronic kidney disease (CKD) is a complex and multifactorial disorder that affects millions of individuals worldwide. The molecular and cellular mechanisms driving CKD pathogenesis remain incompletely understood, hindering the development of targeted therapeutic interventions. In this study, we employ a cutting-edge approach combining single-nucleus RNA sequencing (snRNA-seq) and assay for transposase-accessible chromatin using sequencing (snATAC-seq) to comprehensively dissect the molecular changes associated with CKD. We collected kidney tissue samples from a sex- and age-matched cohort of 80 controls and 17 CKD patients, enabling us to examine the pathogenic alterations across distinct cellular populations. We observed significant differences in the composition of the proximal tubule, injured distal convoluted tubule, and immune cells. From the snRNA-seq analysis, we identified a number of differentially expressed genes (DEGs) and gene regulatory networks within each cell type. Additionally, snATAC-seq allowed us to map the landscape of genome-wide chromatin accessibility in various kidney cells at the single-cell level. The integration of these multimodal datasets facilitated the characterization of regulatory patterns of changes in chromatin accessibility that were highly correlated with DEGs, indicating dynamics in the regulation of gene expression specific to disease-associated cell populations, such as renal tubular cells and immune cells. In conclusion, this study provides a comprehensive catalogue of unique cellular signatures and transcriptional programs involved in the development of CKD using multimodal profiling of kidney cells. Our findings offered a better understanding of the basis of the disease and shed light on potential therapeutic targets and pathways for drug development, paving the way for personalized treatment strategies in patients suffering from this debilitating disease.

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