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CRTC2 Forms Co-condensates with YTHDF2 that Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance (CRTC2-RIPseq)

ABSTRACT: CRTC2 Forms Co-condensates with YTHDF2 that Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance (CRTC2-RIPseq)

PROVIDER: PRJNA1101517 | ENA |

REPOSITORIES: ENA

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CRTC2 Forms Co-condensates with YTHDF2 that Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance (CRTC2-RIPseq)

Project description:As the third most common cause of cancer-related mortality, hepatocellular carcinoma (HCC) is a global health concern. Despite its prevalence, treatment options are limited, underscoring the need to identify potential therapeutic targets and strategies. Here, we identified amplification of CRTC2, situated in the 1q21.3 region, due to copy number alterations in HCC. In a cohort of patients with HCC, CRTC2 protein levels were frequently elevated and correlated with poor prognosis. Genetic depletion of CRTC2 significantly impeded the onset and progression of HCC in mouse models. CRTC2 formed cytoplasmic condensates that recruited the m6A reader YTHDF2. Furthermore, CRTC2 promoted the translocation of m6A-modified mRNAs from decay sites to polyribosomes by interacting with PABP1. The activities of CRTC2 counteracted YTHDF2-mediated mRNA degradation to enhance the translational efficiency of specific mRNAs, including those encoding LRP5 and c-Jun. Targeting CRTC2 in hepatocytes using AAV8.sgCRTC2 elicited substantial therapeutic benefits in HCC mouse model and significantly enhanced the sensitivity to lenvatinib. Together, this research elucidates the pivotal role and underlying molecular mechanisms of CRTC2 in hepatocarcinogenesis and lenvatinib-resistance, highlighting its potential clinical and therapeutic applications.

2025-02-08 | GSE264239 | GEO

CRTC2 Forms Co-condensates with YTHDF2 that Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance (YTHDF2-RIPseq)

2025-02-08 | GSE264246 | GEO

CRTC2 Forms Co-condensates with YTHDF2 that Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance (RNA-seq)

2025-02-10 | GSE289166 | GEO

CRTC2 Forms Co-condensates with YTHDF2 that Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance (m6A-seq)

2025-02-08 | GSE264244 | GEO

CRTC2 Forms Co-condensates with YTHDF2 that Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance (YTHDF2-RIPseq)

Project description:CRTC2 Forms Co-condensates with YTHDF2 that Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance (YTHDF2-RIPseq)

| PRJNA1101539 | ENA

CRTC2 Forms Co-condensates with YTHDF2 that Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance (RNA-seq)

Project description:CRTC2 Forms Co-condensates with YTHDF2 that Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance (RNA-seq)

| PRJNA1221846 | ENA

CRTC2 Forms Co-condensates with YTHDF2 that Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance (m6A-seq)

Project description:CRTC2 Forms Co-condensates with YTHDF2 that Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance (m6A-seq)

| PRJNA1101528 | ENA

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