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Enhancer regulation in kidney epithelial cells
Jakub Jankowski
Julia Wilflingseder
Reinhold Erben
Lothar Hennighausen
PhD Thesis - Veterinärmedizinische Universität Wien - 2022
PhD thesis - University of Veterinary Medicine Vienna - 2022
Epigenetics drive an often underestimated set of mechanisms governing the fundamental regulation of gene expression. Selective availability of chromatin not only dictates cell differentiation and identity, but can drastically change, as pathological conditions are a potent catalyst for shifts in epigenetic landscape. Our studies show how renal injury is not an exception and aim to investigate how the transcription patterns of the kidney epithelium change in response to an insult. First, we analyzed renal epithelial response to cytokine stimulation to help elucidate the potential effects of SARS-CoV-2 on the kidney. Our work was the first to show that interferons induce expression of an alternative ACE2 isoform, dACE2, in renal epithelium, but not the canonical protein, showing bias of earlier reports and indicating the need of careful study of the genetic loci of known disease-related genes. We also generated and compared a wide range of the next-generation sequencing datasets pertaining to tubular response to proinflammatory stimuli. We show that distinct transcription programs are enabled in response to interferons and injury models, and that they differ between stimulated tissues. Our results clearly show how non-homogenous the term renal inflammation is and indicate how much its attenuation may need to be adjusted based on the injury’s origin. Second, we used an ischemic acute kidney injury model to investigate the dynamic changes in the entire epigenetic landscape of mouse kidney. We showed hundreds of promoter and candidate enhancer elements gaining or losing their activity in the early repair phase following renal insult, as well as identified transcription factors driving this process. We used compounds disrupting RNA transcription and observed that they can partly inhibit the repair of the epithelial cells, but also attenuate fibrosis. This study provides first insight into the robustness of the epigenetic changes renal cells undergo to initiate repair mechanisms, as well as indicate that timing is a key factor for therapeutic strategies aiming adjust them. These discoveries further our understanding of the extent, variability and regulation of epigenetic landscape of the kidney. They will aid in development of novel therapeutic strategies aiming to combat diseases and adverse physiological processes in the kidney.
Englisch
2022
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