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CAMP-induced nuclear condensation of CRTC2 promotes transcription elongation and cystogenesis in autosomal dominant polycystic kidney disease

ABSTRACT: cAMP-induced nuclear condensation of CRTC2 promotes transcription elongation and cystogenesis in autosomal dominant polycystic kidney disease

PROVIDER: PRJNA726728 | ENA |

REPOSITORIES: ENA

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cAMP-induced nuclear condensation of CRTC2 promotes transcription elongation and cystogenesis in autosomal dominant polycystic kidney disease

Project description: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 we report that CREB-regulated transcription coactivator 2 (CRTC2) translocates to the nucleus and forms phase-separated condensates upon activation of cAMP signaling. We 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). We 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, we 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, our findings elucidate a mechanism by which CRTC2 nuclear condensation conveys cAMP signaling to transcription elongation activation and thereby promotes cystogenesis in ADPKD.

2021-12-28 | GSE173695 | GEO

cAMP-induced nuclear condensation of CRTC2 promotes transcription elongation and cystogenesis in autosomal dominant polycystic kidney disease (ChIP-Seq)

Project description:Forming 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 signaling transduction and gene activation through condensate formation and how dysregulation of these mechanisms contributes to disease progression remain elusive. Here we report that CREB-regulated transcription coactivator 2 (CRTC2) translocates to nucleus and forms phase-separated condensates upon activation of cAMP signaling. We show that CRTC2 interacts with positive transcription elongation factor b (P-TEFb), and cAMP-induced CRTC2 condensate formation activates P-TEFb by extracting P-TEFb from its inhibitory complex. Aberrantly elevated cAMP signaling plays central roles in the development of autosomal dominant polycystic kidney disease (ADPKD). We demonstrate that, in contrast to a dispersed cytosolic distribution in the normal tubular epithelia cells, CRTC2 localizes in nucleus and forms condensates in cystic epithelial cells of mouse and human ADPKD kidneys. We show that genetic depletion of CRTC2 markedly suppresses cyst growth in an orthologous ADPKD mouse model. Using integrative transcriptomic and cistromic analyses, we identify CRTC2-regulated cystogenic genes, whose activation depends on CRTC2 condensation-facilitated P-TEFb recruitment and RNA polymerase II pausing release. Together, our findings elucidate a mechanism by which CRTC2 nuclear condensation conveys cAMP signaling to transcription elongation activation and promotes cystogenesis in ADPKD.

2021-12-28 | GSE173694 | GEO

cAMP-induced nuclear condensation of CRTC2 promotes transcription elongation and cystogenesis in autosomal dominant polycystic kidney disease (RNA-Seq)

2021-12-28 | GSE173693 | GEO

cAMP-induced nuclear condensation of CRTC2 promotes transcription elongation and cystogenesis in autosomal dominant polycystic kidney disease (RNA-Seq)

Project description:cAMP-induced nuclear condensation of CRTC2 promotes transcription elongation and cystogenesis in autosomal dominant polycystic kidney disease (RNA-Seq)

| PRJNA726727 | ENA

cAMP-induced nuclear condensation of CRTC2 promotes transcription elongation and cystogenesis in autosomal dominant polycystic kidney disease (ChIP-Seq)

Project description:cAMP-induced nuclear condensation of CRTC2 promotes transcription elongation and cystogenesis in autosomal dominant polycystic kidney disease (ChIP-Seq)

| PRJNA726730 | ENA

Nuclear condensation of CDYL links histone crotonylation and cystogenesis in autosomal dominant polycystic kidney disease

Project description:Nuclear condensation of CDYL links histone crotonylation and cystogenesis in autosomal dominant polycystic kidney disease

| PRJNA761102 | ENA

Nuclear condensation of CDYL links histone crotonylation and cystogenesis in autosomal dominant polycystic kidney disease [RNA-Seq]

Project description:Nuclear condensation of CDYL links histone crotonylation and cystogenesis in autosomal dominant polycystic kidney disease [RNA-Seq]

| PRJNA761104 | ENA

Nuclear condensation of CDYL links histone crotonylation and cystogenesis in autosomal dominant polycystic kidney disease [ChIP-Seq]

Project description:Nuclear condensation of CDYL links histone crotonylation and cystogenesis in autosomal dominant polycystic kidney disease [ChIP-Seq]

| PRJNA761105 | ENA

Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease (RNA-Seq)

Project description:We showed that pharmacological inhibition of P-TEFb attenuated cyst development in ADPKD mouse models. Genome-wide analyses demonstrated that P-TEFb inhibition abrogated transcriptional pause release and suppressed a pathologic gene expression program during cystogenesis. This work revealed a mechanism by which aberrant activation of P-TEFb-mediated transcription elongation promotes cystogenesis in ADPKD.

2019-06-20 | GSE128522 | GEO

Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease (ChIP-Seq)

2019-06-20 | GSE128521 | GEO

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