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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE183512 | GEO | 2022/05/24

REPOSITORIES: GEO

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

Project description:Background:molecular mechanisms coupling cellular metabolisms with the epigenome in cystic cells remains largely unknown Methods:To investigate the molecular mechanisms underlying the suppression of cyst growth by CDYL overexpression, we generated an engineered ADPKD cell line by stably expressing CDYL with TY1 tag in WT 9-12 human ADPKD cells (CDYL OE). We profiled genome-wide distribution of CDYL through chromatin immunoprecipitation coupled with sequencing (ChIP-seq) analysis in both parental WT 9-12 cells (control) and CDYL OE cells. Genetic overexpression of CDYL reduces histone Kcr. We examined histone Kcr on CDYL-target genes by performing ChIP-seq analyses using antibody recognizing PanKcr and H3K18cr in control and CDYL OE cells. Results: Using integrative cistromic and transcriptomic analyses, CDYL-regulated cyst-associated genes are identified, whose downregulation depends on CDYL-mediated suppression of histone Kcr. Conclusions: Thus, through establishing a metabolic niche via nuclear condensation, CDYL connects metabolic changes to transcriptional response via histone Kcr in ADPKD.

2022-05-24 | GSE183510 | GEO

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

2022-05-24 | GSE183511 | GEO

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

Project description:We identify the Kcr sites on histones that are targeted by CDYL in ADPKD cells (WT9-12 cells). We chose to knock out CDYL in WT 9-12 cells (CDYL KO) through CRISPR/Cas9-mediated gene editing to increase the overall levels of histone Kcr. We quantified Kcr modifications on different histone residues in CDYL KO versus parental WT 9-12 cells (control) using high-resolution liquid chromatography tandem mass spectrometry (LC-MS/MS)-based proteomics analysis

2022-01-17 | PXD031029 |

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

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, 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.

| S-EPMC8981427 | biostudies-literature

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