Universität zu Köln

Chen, He ORCID: 0000-0002-7616-8438 (2024). Transcriptional Regulation and Epigenetic Landscape of the Glomerulus. PhD thesis, Universität zu Köln.

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Abstract

Disease heterogeneity presents challenges in the understanding of disease progression of individual cells or cell types within complex tissues, particularly when the cells that are undergoing damage progress at different rates. In progressive renal diseases that lead to focal segmental glomerulosclerosis (FSGS), the loss of podocyte number and function is a major contributing factor for renal pathogenesis and our understanding of the underlying damage mechanisms in damaged podocytes has been limited. The present work addresses this gap in understanding by investigating the dysregulation of transcription networks, alterations in the epigenetic landscape, modulation of cellular pathways, and regulation by transcription factor (TF) in podocytes during FSGS development. By employing mouse models, single-cell technologies, and molecular assays, we developed a podocyte damage score (PDS) to decipher TF and pathway rewiring, explored changes in the epigenetic landscape, and investigated the molecular actions of LMX1B, which is a key TF essential for podocyte maintenance. Our findings highlighted the robustness and specificity of the PDS in scoring damage at single-cell resolution across murine and human chronic kidney diseases and demonstrated the versatility of the PDS in identifying unique cellular mechanisms across diverse disease models. We performed comprehensive mappings of the epigenetic landscape for various glomerular cell types in health and disease and revealed differential regulation of glomerular cell-specific enhancers through chromatin accessibility and by acetylation of histone 3 lysine 27 which correlated with target gene expression and key signaling pathways. Additionally, functional podocyte-specific knockout studies of Lmx1b using single-cell multiomic approaches revealed its potential role as a novel regulator of the non-canonical Wnt signaling pathway in injured podocytes and in vitro studies implicated the C-terminal end of LMX1B in liquid-liquid phase separation (LLPS), and offered additional mechanistic insight into the function of LMX1B. In summary, our integrated approach utilizing single-cell technology allowed for a comprehensive investigation of the intricate gene regulatory mechanisms and epigenetic rewiring of podocytes undergoing FSGS and shed light on differential regulation related to key TFs and signaling pathways critical for podocyte function.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Chen, He he.chen@uk-koeln.de orcid.org/0000-0002-7616-8438 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-731200
Date:	2024
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases
Subjects:	Natural sciences and mathematics
Uncontrolled Keywords:	Keywords Language kidney UNSPECIFIED FSGS UNSPECIFIED epigenetics UNSPECIFIED
Date of oral exam:	11 June 2024
Referee:	Name Academic Title Benzing, Thomas Prof. Dr. Gehring, Niels Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/73120