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CCG-1423-derived compounds reduce global RNA synthesis and inhibit transcriptional responses (ChIP-seq)

ABSTRACT: CCG-1423-derived compounds reduce global RNA synthesis and inhibit transcriptional responses (ChIP-seq)

PROVIDER: PRJNA1020195 | ENA |

REPOSITORIES: ENA

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CCG-1423-derived compounds reduce global RNA synthesis and inhibit transcriptional responses (PRO-seq)

Project description:Myocardin-related transcription factors (MRTFs) are coactivators of serum response factor (SRF), and thereby regulate cytoskeletal gene expression in response to actin dynamics. MRTFs have also been implicated in heat shock protein (hsp) transcription in fly ovaries, but the mechanisms remain unclear. Here we demonstrate that in mammalian cells, MRTFs are dispensable for hsp gene induction. However, the widely used small molecule inhibitors of MRTF/SRF transcription pathway, derived from CCG-1423, efficiently inhibit hsp gene transcription in both fly and mammalian cells also in absence of MRTFs. Quantifying RNA synthesis and RNA polymerase distribution demonstrates that CCG-1423-derived compounds have a genome-wide effect on transcription. Indeed, tracking nascent transcription at nucleotide resolution reveals that CCG-1423-derived compounds reduce RNA polymerase II elongation, and severely dampen the transcriptional response to heat shock. The effects of CCG-1423-derived compounds therefore extend beyond the MRTF/SRF pathway into nascent transcription, opening novel opportunities for their use in transcription research.

2023-10-03 | GSE244231 | GEO

CCG-1423-derived compounds reduce global RNA synthesis and inhibit transcriptional responses (ChIP-seq)

2023-09-26 | GSE243873 | GEO

CCG-1423-derived compounds reduce global RNA synthesis and inhibit transcriptional responses

Project description:CCG-1423-derived compounds reduce global RNA synthesis and inhibit transcriptional responses

| PRJNA1021946 | ENA

CCG-1423-derived compounds reduce global RNA synthesis and inhibit transcriptional responses (PRO-seq)

Project description:CCG-1423-derived compounds reduce global RNA synthesis and inhibit transcriptional responses (PRO-seq)

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Rho transcription inhibitor CCG-1423 effect on PC-3 cells

Project description:Analysis of serum starved PC-3 cells treated with CCG-1423, Latrunculin B, or the transcription elongation inhibitor DRB for 2 or 24 hours. Results provide insights to potential therapeutic approaches to cancer metastasis. Twenty one samples in triplicate were analyzed and compared to the DMSO-treated control. The primary condition tested was the effect of the Rho-transcription pathway inhibitor, CCG-1423 As a biologically related control, the actin polymerization inhibitor, Latrunculin B, that also blocks Rho-stimulated gene transcription was tested. As a control for non-specific transcription inhibition, DRB was used. All samples, 2-hr and 24-hr treated samples were compared to the 24-hr DMSO sample.

2013-05-01 | E-GEOD-30188 | biostudies-arrayexpress

CCG-1423-derived compounds reduce global RNA synthesis and inhibit transcriptional responses

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-09-28 | GSE244232 | GEO

Rho transcription inhibitor CCG-1423 effect on PC-3 cells

2013-05-01 | GSE30188 | GEO

Identification of Pirin as a Molecular Target of the CCG-1423/CCG-203971 Series of Antifibrotic and Antimetastatic Compounds.

Project description:A series of compounds (including CCG-1423 and CCG-203971) discovered through an MRTF/SRF-dependent luciferase screen has shown remarkable efficacy in a variety of in vitro and in vivo models, including significant reduction of melanoma metastasis and bleomycin- induced fibrosis. Although these compounds are efficacious in these disease models, the molecular target is unknown. Here, we describe affinity isolation-based target identification efforts which yielded pirin, an iron-dependent cotranscription factor, as a target of this series of compounds. Using biophysical techniques including isothermal titration calorimetry and X-ray crystallography, we verify that pirin binds these compounds in vitro. We also show with genetic approaches that pirin modulates MRTF- dependent luciferase reporter activity. Finally, using both siRNA and a previously validated pirin inhibitor, we show a role for pirin in TGF-β- induced gene expression in primary dermal fibroblasts. A recently developed analog, CCG-257081, which co crystallizes with pirin, is also effective in the prevention of bleomycin-induced dermal fibrosis.

| S-EPMC7006939 | biostudies-literature

CCg Progenitors

Project description:Experiment comparing Low-density, CCg derived, progenitors (LDP) with high-density progenitors (HDP), and neurons (LDN) and astrocytes (LDA) derived from the LDP condition Keywords: other

2005-06-16 | GSE2499 | GEO

Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onset

Project description:About one third of dilated cardiomyopathy (DCM) cases are caused by mutations in sarcomere or cytoskeletal proteins. Yet treating the cytoskeleton directly is not possible because drugs that bind to actin are not well tolerated. Mutations in the actin binding protein CAP2 can cause DCM and knockout mice, either whole body (CAP2 KO) or cardiomyocyte specific knockouts (CAP2 CKO), develop DCM with cardiac conduction disease. RNA-seq analysis of CAP2 KO hearts and isolated cardiomyocytes revealed over-activation of fetal genes including serum response factor (SRF) regulated genes such as Myl9 and Acta2 prior to the emergence of cardiac disease. To test if we could treat CAP2 KO mice, we synthesized and tested the SRF inhibitor CCG-1423-8u. CCG-1423-8u reduced expression of the SRF targets Myl9 and Acta2, as well as the biomarker of heart failure, NPPA. The median survival of CAP2 CKO mice was 98 days, while CCG-1423-8u treated CKO mice survived for 116 days and also maintain normal cardiac function longer. These results suggest that some forms of sudden cardiac death and cardiac conduction disease are under cytoskeletal stress and that inhibiting signaling through SRF may benefit DCM by reducing cytoskeletal stress.

2019-02-22 | GSE125603 | GEO

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