P02: Clonal evolution of somatic mosaicism during acute-to-chronic kidney disease progression
Open postions: 1 Postdoctoral researcher for 2 years and 1 PhD student
Principal investigators: Dr. Sanders and Prof. Dr. Schmidt-Ott
Acute kidney injury (AKI) is commonly observed in critically ill individuals and results in a greatly increased risk of progressive chronic kidney disease or death. AKI is initiated by complex pathophysiological processes that include inflammation, ischemia, hypoxia, and/or toxin exposure. AKI results in widespread cell death of the cells of the renal tubule. Surviving cells then proliferate clonally and repair the injured kidney tubule. The repeated cycles of cellular stress, injury, proliferation, and recovery may predispose kidney cells to disease-promoting somatic mutations. Somatic mutations in renal cells can generate genetically distinct cell populations (i.e., subclones) that result in tissue-specific ‘somatic mosaicism’. When these mutations disrupt key epigenetic and transcriptional programs, they can give rise to pathogenic subclones with distinct disease phenotypes and mechanisms. This hypothesis is supported by evidence of increased genomic instability in kidney disease and by the propensity of patients with acute kidney injury or chronic kidney disease to develop renal tumors. However, the role of acquired somatic mosaicism in kidney tissue and its potential pathophysiological implications are incompletely understood. The project combined single-cell and strand-specific DNA sequencing (i.e., Strand-seq) with assay for transposase-accessible chromatin (ATAC) and single-nucleus RNA sequencing from kidney cells and tissues to investigate the development and consequences of somatic mosaicism at the single-cell level. The key goal is to identify the types and frequency of acquired somatic structural variants such as deletions, insertions, inversions, and other genomic rearrangements and correlate them with changes in genome-wide nucleosome occupancy, chromatin accessibility, and gene expression in kidney cells. Experimental conditions (in vivo ischemia-reperfusion injury in mouse kidneys and in vitro simulated hypoxia of kidney cells) will be combined with clinical samples of kidney cells excreted in urine from patients with acute or chronic kidney disease. The putative effects of somatic structural variants on renal cell proliferation, cell death, and gene expression will be validated by experimental modeling of variant-associated molecular perturbations in kidney cells. The study has the potential to uncover novel molecular links between acquired somatic genomic alterations in kidney cells and disease-promoting dysregulation of gene expression control.