Emerging evidence indicates that epigenetic modulation of gene expression plays a key role in the progression of autosomal dominant polycystic kidney disease (ADPKD). However, the molecular basis for how the altered epigenome modulates transcriptional responses, and thereby disease progression in ADPKD, remains largely unknown.

Kidneys from control and ADPKD mice were examined for the expression of CDYL and histone acylations. CDYL expression and its correlation with disease severity were analyzed in a cohort of patients with ADPKD. Cdyl transgenic mice were crossed with Pkd1 knockout mice to explore CDYL’s role in ADPKD progression. Integrated cistromic and transcriptomic analyses were performed to identify direct CDYL target genes. High-sensitivity mass spectrometry analyses were undertaken to characterize CDYL-regulated histone lysine crotonylations (Kcr). Biochemical analysis and zebrafish models were used for investigating CDYL phase separation.

CDYL was downregulated in ADPKD kidneys, accompanied by an increase of histone Kcr. Genetic overexpression of Cdyl reduced histone Kcr and slowed cyst growth. We identified CDYL-regulated cyst-associated genes, whose downregulation depended on CDYL-mediated suppression of histone Kcr. CDYL assembled nuclear condensates through liquid-liquid phase separation in cultured kidney epithelial cells and in normal kidney tissues. The phase-separating capacity of CDYL was required for efficient suppression of locus-specific histone Kcr, of expression of its target genes, and of cyst growth.

These results elucidate a mechanism by which CDYL nuclear condensation links histone Kcr to transcriptional responses and cystogenesis in ADPKD.

新的证据表明，基因表达的表观遗传调节在常染色体显性多囊肾病（ADPKD）的进展中发挥着关键作用。然而，改变的表观基因组如何调节转录反应，从而调节 ADPKD 疾病进展的分子基础仍然很大程度上未知。

检查对照小鼠和 ADPKD 小鼠的肾脏 CDYL 和组蛋白酰化的表达。在一组 ADPKD 患者中分析了 CDYL 表达及其与疾病严重程度的相关性。将Cdyl转基因小鼠与Pkd1敲除小鼠杂交，以探索 CDYL 在 ADPKD 进展中的作用。进行整合的顺反体和转录组分析来鉴定直接的 CDYL 靶基因。采用高灵敏度质谱分析来表征 CDYL 调节的组蛋白赖氨酸巴豆酰化 (Kcr)。生化分析和斑马鱼模型用于研究 CDYL 相分离。

CDYL 在 ADPKD 肾脏中下调，并伴有组蛋白 Kcr 增加。Cdyl的基因过度表达会降低组蛋白 Kcr 并减缓囊肿生长。我们鉴定了 CDYL 调节的囊肿相关基因，其下调取决于 CDYL 介导的组蛋白 Kcr 抑制。CDYL 在培养的肾上皮细胞和正常肾组织中通过液-液相分离组装核凝聚物。CDYL 的相分离能力对于有效抑制位点特异性组蛋白 Kcr、其靶基因的表达以及囊肿生长是必需的。

这些结果阐明了 CDYL 核凝结将组蛋白 Kcr 与 ADPKD 转录反应和囊肿发生联系起来的机制。