Cell-type specific gene regulatory programs associated with autosomal dominant polycystic kidney disease

• Applicants: Professor Dr. Michael Köttgen; Dr. Sebastian Preißl
• Subject Area: Nephrology ; General Genetics and Functional Genome Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 514085945

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of kidney failure affecting more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation - a focal process arising from individual renal epithelial cells upon somatic loss of heterozygosity of the respective genes. This leads to substantial cellular remodeling and subsequent immune cell infiltration of kidneys. Cell-type specific gene expression patterns and dynamics are regulated by cis-regulatory elements (CREs) such as promoters and enhancers. CREs are characterized by the presence of accessible chromatin and their activity can be modulated by transcription factors. ADPKD mouse models using conditional Pkd1 inactivation faithfully recapitulate the human disease. One main advantage of such a mouse model is the precise timing of Pkd1 gene inactivation allowing for the study of early transcriptional and epigenomic alterations and changes during disease progression This is not possible in human samples that are usually collected from patients with end-stage disease. Bulk transcriptomic analyses have been used to investigate transcriptional dysregulation and disease mechanisms in mice and humans. However, these studies cannot resolve the cellular complexity of the disease. Single cell genomics assays can overcome this limitation. Here, we will use joint profiling of transcriptomes and chromatin accessibility from the same cell to identify gene regulatory programs and transcription factors involved in cellular remodeling whereby Pkd1 deletion leads to ADPKD. We will investigate disease initiation and progression at defined time points after Pkd1 gene inactivation. The specific aims of this project are to 1) identify early cell-type-specific gene-regulatory programs during cyst initiation, 2) analyze the time course and gene regulatory mechanisms underlying kidney cell remodeling during disease progression, and 3) determine the time course of immune cell infiltration and map the crosstalk between epithelial and immune cells during ADPKD progression. We expected that the proposed study will provide comprehensive insight into the cellular remodeling during ADPKD and the underlying epigenomic and transcriptional programs. A better understanding of disease-relevant molecular pathways in ADPKD will help to develop novel therapeutic approaches.

• DFG Programme: Research Grants