cAMP-Induced Nuclear Condensation of CRTC2 Promotes Transcription Elongation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease.
cAMP-Induced Nuclear Condensation of CRTC2 Promotes Transcription Elongation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease.
复制标题
DOI：
10.1002/advs.202104578
复制
发表时间：
2022-04
期刊：
影响因子：
--
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Mi Z;Song Y;Wang J;Liu Z;Cao X;Dang L;Lu Y;Sun Y;Xiong H;Zhang L;Chen Y
通过相分离形成生物分子凝聚体最近已成为响应细胞外信号传导调节基因表达的新原理。然而，信号转导和基因激活通过冷凝物形成耦合的分子机制，以及这些机制的失调如何导致疾病进展，仍然难以捉摸。在这里，作者报告说，CREB 调节的转录辅激活因子 2 (CRTC2) 在 cAMP 信号传导激活后易位到细胞核并形成相分离的凝聚物。他们表明，核内 CRTC2 与正转录延伸因子 b (P-TEFb) 相互作用，并通过破坏抑制性 7SK snRNP 复合物来激活 P-TEFb。 cAMP 信号异常升高在常染色体显性多囊肾病 (ADPKD) 的发展中发挥着核心作用。他们发现 CRTC2 定位于细胞核，并在小鼠和人类 ADPKD 肾脏的囊性上皮细胞中形成凝聚物。 CRTC2 的基因缺失可抑制直系同源 ADPKD 小鼠模型中的囊肿生长。通过综合转录组学和顺反组学分析，他们鉴定了 CRTC2 调节的囊肿发生相关基因，其激活取决于 CRTC2 冷凝物促进的 P-TEFb 募集和暂停的 RNA 聚合酶 II 的释放。他们的研究结果共同阐明了 CRTC2 核浓缩将 cAMP 信号传导至转录延伸激活，从而促进 ADPKD 囊肿发生的机制。生物分子缩合物在响应内部和外部信号控制基因表达方面发挥着关键作用。这项研究阐明了 CRTC2 核浓缩将 cAMP 信号传递至常染色体显性多囊肾病中转录延伸激活和囊肿发生的机制。
Formation of biomolecular condensates by phase separation has recently emerged as a new principle for regulating gene expression in response to extracellular signaling. However, the molecular mechanisms underlying the coupling of signal transduction and gene activation through condensate formation, and how dysregulation of these mechanisms contributes to disease progression, remain elusive. Here, the authors report that CREB‐regulated transcription coactivator 2 (CRTC2) translocates to the nucleus and forms phase‐separated condensates upon activation of cAMP signaling. They show that intranuclear CRTC2 interacts with positive transcription elongation factor b (P‐TEFb) and activates P‐TEFb by disrupting the inhibitory 7SK snRNP complex. Aberrantly elevated cAMP signaling plays central roles in the development of autosomal dominant polycystic kidney disease (ADPKD). They find that CRTC2 localizes to the nucleus and forms condensates in cystic epithelial cells of both mouse and human ADPKD kidneys. Genetic depletion of CRTC2 suppresses cyst growth in an orthologous ADPKD mouse model. Using integrative transcriptomic and cistromic analyses, they identify CRTC2‐regulated cystogenesis‐associated genes, whose activation depends on CRTC2 condensate‐facilitated P‐TEFb recruitment and the release of paused RNA polymerase II. Together, their findings elucidate a mechanism by which CRTC2 nuclear condensation conveys cAMP signaling to transcription elongation activation and thereby promotes cystogenesis in ADPKD. Biomolecular condensates play key roles in controlling gene expression in response to internal and external signals. This study elucidates a mechanism by which CRTC2 nuclear condensation conveys cAMP signaling to transcription elongation activation and cystogenesis in autosomal dominant polycystic kidney disease.
登录
查看更多内容
影响因子：
29
作者：
Erion DM;Ignatova ID;Yonemitsu S;Nagai Y;Chatterjee P;Weismann D;Hsiao JJ;Zhang D;Iwasaki T;Stark R;Flannery C;Kahn M;Carmean CM;Yu XX;Murray SF;Bhanot S;Monia BP;Cline GW;Samuel VT;Shulman GI
通讯作者：
Shulman GI
DOI：
10.1038/nrm3072
发表时间：
2011-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
ENL 启动超延伸复合物 (SEC) 的多价相分离来控制快速转录激活
影响因子：
13.6
作者：
Guo, Chenghao;Che, Zhuanzhuan;Lin, Chengqi
通讯作者：
Lin, Chengqi
DOI：
10.1073/pnas.91.18.8517
发表时间：
1994-08-30
影响因子：
11.1
作者：
ARONICA, SM;KRAUS, WL;KATZENELLENBOGEN, BS
通讯作者：
KATZENELLENBOGEN, BS
影响因子：
16.6
作者：
Gabryelczyk, Bartosz;Cai, Hao;Miserez, Ali
通讯作者：
Miserez, Ali