Nuclear Condensation of CDYL Links Histone Crotonylation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease

Recent studies support a critical role of epigenetics in cyst-associated gene expression and the progression of autosomal dominant polycystic kidney disease (ADPKD), although the underlying molecular mechanisms remain elusive. Here, we show that expression of CDYL, a chromodomain Y-like transcription repressor and crotonyl-CoA hydratase, is suppressed in ADPKD kidneys, accompanied by an increase of histone lysine crotonylation (Kcr). Interestingly, CDYL can form biomolecular condensates, which enhance its catalytic activity on histone Kcr. Through a phase separation?mediated mechanism, overexpression of CDYL reduces histone Kcr, inhibits the expression of cyst-associated genes, and slows cyst growth. Thus, our study establishes a prominent role for CDYL nuclear condensation in regulating histone Kcr, the cyst-associated gene expression program, and ADPKD progression.