cAMP‐Induced Nuclear Condensation of CRTC2 Promotes Transcription Elongation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease
Abstract 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 fo...
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| Format: | Article |
| Language: | English |
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Wiley
2022-04-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202104578 |
| _version_ | 1811297658724155392 |
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| author | Zeyun Mi Yandong Song Jiuchen Wang Zhiheng Liu Xinyi Cao Lin Dang Yumei Lu Yongzhan Sun Hui Xiong Lirong Zhang Yupeng Chen |
| author_facet | Zeyun Mi Yandong Song Jiuchen Wang Zhiheng Liu Xinyi Cao Lin Dang Yumei Lu Yongzhan Sun Hui Xiong Lirong Zhang Yupeng Chen |
| author_sort | Zeyun Mi |
| collection | DOAJ |
| description | Abstract 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. |
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| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-13T06:08:27Z |
| publishDate | 2022-04-01 |
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| series | Advanced Science |
| spelling | doaj.art-fd59fb12c55643bead4caa0dc0c32cc32022-12-22T02:59:11ZengWileyAdvanced Science2198-38442022-04-01910n/an/a10.1002/advs.202104578cAMP‐Induced Nuclear Condensation of CRTC2 Promotes Transcription Elongation and Cystogenesis in Autosomal Dominant Polycystic Kidney DiseaseZeyun Mi0Yandong Song1Jiuchen Wang2Zhiheng Liu3Xinyi Cao4Lin Dang5Yumei Lu6Yongzhan Sun7Hui Xiong8Lirong Zhang9Yupeng Chen10Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Tianjin Institute of Urology The Second Hospital of Tianjin Medical University Tianjin Medical University Tianjin 300070 ChinaKey Laboratory of Immune Microenvironment and Disease (Ministry of Education) The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Tianjin Institute of Urology The Second Hospital of Tianjin Medical University Tianjin Medical University Tianjin 300070 ChinaKey Laboratory of Immune Microenvironment and Disease (Ministry of Education) The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Tianjin Institute of Urology The Second Hospital of Tianjin Medical University Tianjin Medical University Tianjin 300070 ChinaKey Laboratory of Immune Microenvironment and Disease (Ministry of Education) The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Tianjin Institute of Urology The Second Hospital of Tianjin Medical University Tianjin Medical University Tianjin 300070 ChinaKey Laboratory of Immune Microenvironment and Disease (Ministry of Education) The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Tianjin Institute of Urology The Second Hospital of Tianjin Medical University Tianjin Medical University Tianjin 300070 ChinaKey Laboratory of Immune Microenvironment and Disease (Ministry of Education) The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Tianjin Institute of Urology The Second Hospital of Tianjin Medical University Tianjin Medical University Tianjin 300070 ChinaKey Laboratory of Immune Microenvironment and Disease (Ministry of Education) The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Tianjin Institute of Urology The Second Hospital of Tianjin Medical University Tianjin Medical University Tianjin 300070 ChinaKey Laboratory of Immune Microenvironment and Disease (Ministry of Education) The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Tianjin Institute of Urology The Second Hospital of Tianjin Medical University Tianjin Medical University Tianjin 300070 ChinaDepartment of Urology Shandong Provincial Hospital Affiliated to Shandong First Medical University Jinan Shandong 250001 ChinaKey Laboratory of Immune Microenvironment and Disease (Ministry of Education) The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Tianjin Institute of Urology The Second Hospital of Tianjin Medical University Tianjin Medical University Tianjin 300070 ChinaKey Laboratory of Immune Microenvironment and Disease (Ministry of Education) The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Tianjin Institute of Urology The Second Hospital of Tianjin Medical University Tianjin Medical University Tianjin 300070 ChinaAbstract 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.https://doi.org/10.1002/advs.202104578ADPKDcAMPcondensateCRTC2phase separationP‐TEFb |
| spellingShingle | Zeyun Mi Yandong Song Jiuchen Wang Zhiheng Liu Xinyi Cao Lin Dang Yumei Lu Yongzhan Sun Hui Xiong Lirong Zhang Yupeng Chen cAMP‐Induced Nuclear Condensation of CRTC2 Promotes Transcription Elongation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease Advanced Science ADPKD cAMP condensate CRTC2 phase separation P‐TEFb |
| title | cAMP‐Induced Nuclear Condensation of CRTC2 Promotes Transcription Elongation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease |
| title_full | cAMP‐Induced Nuclear Condensation of CRTC2 Promotes Transcription Elongation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease |
| title_fullStr | cAMP‐Induced Nuclear Condensation of CRTC2 Promotes Transcription Elongation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease |
| title_full_unstemmed | cAMP‐Induced Nuclear Condensation of CRTC2 Promotes Transcription Elongation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease |
| title_short | cAMP‐Induced Nuclear Condensation of CRTC2 Promotes Transcription Elongation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease |
| title_sort | camp induced nuclear condensation of crtc2 promotes transcription elongation and cystogenesis in autosomal dominant polycystic kidney disease |
| topic | ADPKD cAMP condensate CRTC2 phase separation P‐TEFb |
| url | https://doi.org/10.1002/advs.202104578 |
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