Unraveling Epigenetic and Immune Mechanisms Underlying Cystogenesis in Autosomal Dominant Polycystic Kidney Disease [ChIP-Seq]

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a prevalent, life-threatening monogenetic disorder that affects millions worldwide. Currently, therapeutic options are limited and often associated with complications. To find more effective treatments, this study aimed to understand the molecular mechanisms driving cystogenesis in ADPKD. By analysing various epigenetic factors, we identified a set of master transcription factors that guided a core regulatory circuitry and remodeled chromatin accessibility in ADPKD. We further explored the role of immune cells, notably macrophages, in the disease’s progression using single-cell RNA sequencing. A subgroup of Lhfpl2+/Fat3+ macrophages, which reactivated the Hgf-Met-Nfkb1-Runx1 pathways, was found essential for cystic cell fate transition. Targeting the identified epigenetic regulators, H3K4me3 and TF Runx1, effectively halted disease progression in a mouse model. These findings may lead to innovative treatments for ADPKD in humans.