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CCG-1423-derived compounds reduce global RNA synthesis and inhibit transcriptional responses
Open accessAbstract
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 transcription of heat shock protein (HSP)-encoding genes in fly ovaries, but the mechanisms remain unclear. Here, we demonstrate that, in mammalian cells, MRTFs are dispensable for gene induction of HSP-encoding genes. However, the widely used small-molecule inhibitors of the MRTF-SRF transcription pathway, derived from CCG-1423, also efficiently inhibit gene transcription of HSP-encoding genes in both fly and mammalian cells in the 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.
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“Nonspecific effects of the CCG inhibitor may be explained because this inhibitor affects the global transcriptional regulation through the inhibition of RNA pol II [43].”
From Mechanical stiffness orchestrates distinct regulation of MRTFs and YAP / TAZ transcriptional cofactors in hepatocytes (2026) · cites this paper as [43]
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“In PH, CCG inhibitors required high concentrations to downregulate MRTcoF protein targets in TCPD (> 75 μm); however, CCG molecules have been reported as inhibiting global transcriptional activation at ≥ 25 μm [43].”
From Mechanical stiffness orchestrates distinct regulation of MRTFs and YAP / TAZ transcriptional cofactors in hepatocytes (2026) · cites this paper as [43]
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Citations
Cites
RNA polymerase II speed: a key player in controlling and adapting transcriptome composition
Muniz, L., Nicolas, E., & Trouche, D. (2021) · The EMBO Journal · doi:10.15252/embj.2020105740 · Cited by 198
Transcriptional response to stress is pre-wired by promoter and enhancer architecture
Vihervaara, A., Mahat, D. B., Guertin, M. J., Chu, T., Danko, C. G., Lis, J. T., & Sistonen, L. (2017) · Nature Communications · doi:10.1038/s41467-017-00151-0 · Cited by 164
Self-citation
Research works printed but not linked: 60
- Bell, 2013, Optimization of novel nipecotic bis(amide) inhibitors of the Rho/MKL1/SRF transcriptional pathway as potential anti-metastasis agents, Bioorg. Med. Chem. Lett., 23, 3826, 10.1016/j.bmcl.2013.04.080 · DOI
- Berg, 2012, U1 snRNP determines mRNA length and regulates isoform expression, Cell, 150, 53, 10.1016/j.cell.2012.05.029 · DOI
- Booth, 2018, Cdk9 regulates a promoter-proximal checkpoint to modulate RNA polymerase II elongation rate in fission yeast, Nat. Commun., 9, 543, 10.1038/s41467-018-03006-4 · DOI
- Brandt, 2009, Regulation of myocardin-related transcriptional coactivators through cofactor interactions in differentiation and cancer, Cell Cycle, 8, 2523, 10.4161/cc.8.16.9398 · DOI
- Cheeseman, 2017, Discovery of a chemical probe bisamide (CCT251236): an orally bioavailable efficacious pirin ligand from a heat shock transcription factor 1 (HSF1) phenotypic screen, J. Med. Chem., 60, 180, 10.1021/acs.jmedchem.6b01055 · DOI
- Chu, 2018, Chromatin run-on and sequencing maps the transcriptional regulatory landscape of glioblastoma multiforme, Nat. Genet., 50, 1553, 10.1038/s41588-018-0244-3 · DOI
- Cohen, 1985, Separate regulatory elements for the heat-inducible and ovarian expression of the Drosophila hsp26 gene, Cell, 43, 737, 10.1016/0092-8674(85)90247-8 · DOI
- Cugusi, 2022, Heat shock induces premature transcript termination and reconfigures the human transcriptome, Mol. Cell, 82, 1573, 10.1016/j.molcel.2022.01.007 · DOI
- Dennis, 2003, DAVID: Database for Annotation, Visualization, and Integrated Discovery, Genome Biol., 4, P3, 10.1186/gb-2003-4-5-p3 · DOI · Paper page
- Duarte, 2016, Transcription factors GAF and HSF act at distinct regulatory steps to modulate stress-induced gene activation, Genes Dev., 30, 1731, 10.1101/gad.284430.116 · DOI
- Esnault, 2014, Rho-actin signaling to the MRTF coactivators dominates the immediate transcriptional response to serum in fibroblasts, Genes Dev., 28, 943, 10.1101/gad.239327.114 · DOI
- Evelyn, 2007, CCG-1423: a small-molecule inhibitor of RhoA transcriptional signaling, Mol. Cancer Ther., 6, 2249, 10.1158/1535-7163.MCT-06-0782 · DOI
- Evelyn, 2016, Small-molecule inhibition of Rho/MKL/SRF transcription in prostate cancer cells: modulation of cell cycle, ER stress, and metastasis gene networks, Microarrays, 5, 13, 10.3390/microarrays5020013 · DOI
- Gau, 2022, Myocardin-related transcription factor's interaction with serum-response factor is critical for outgrowth initiation, progression, and metastatic colonization of breast cancer cells, FASEB Bioadv., 4, 509, 10.1096/fba.2021-00113 · DOI
- Geneste, 2002, LIM kinase and Diaphanous cooperate to regulate serum response factor and actin dynamics, J. Cell Biol., 157, 831, 10.1083/jcb.200203126 · DOI
- Guettler, 2008, RPEL motifs link the serum response factor cofactor MAL but not myocardin to Rho signaling via actin binding, Mol. Cell. Biol., 28, 732, 10.1128/MCB.01623-07 · DOI
- Haak, 2017, Pharmacological inhibition of myocardin-related transcription factor pathway blocks lung metastases of RhoC-overexpressing melanoma, Mol. Cancer Ther., 16, 193, 10.1158/1535-7163.MCT-16-0482 · DOI
- Haeussler, 2016, Evaluation of off-target and on-target scoring algorithms and integration into the guide RNA selection tool CRISPOR, Genome Biol., 17, 148, 10.1186/s13059-016-1012-2 · DOI · Paper page
- Hayashi, 2014, RPEL proteins are the molecular targets for CCG-1423, an inhibitor of Rho signaling, PLoS ONE, 9, e89016, 10.1371/journal.pone.0089016 · DOI
- Henriques, 2013, Stable pausing by RNA polymerase II provides an opportunity to target and integrate regulatory signals, Mol. Cell, 52, 517, 10.1016/j.molcel.2013.10.001 · DOI · Paper page
- Himanen, 2022, HSFs drive transcription of distinct genes and enhancers during oxidative stress and heat shock, Nucleic Acids Res., 50, 6102, 10.1093/nar/gkac493 · DOI
- Johnson, 2014, Novel Rho/MRTF/SRF inhibitors block matrix-stiffness and TGF-beta-induced fibrogenesis in human colonic myofibroblasts, Inflamm. Bowel Dis., 20, 154, 10.1097/01.MIB.0000437615.98881.31 · DOI
- Kallio, 2011, Chipster: user-friendly analysis software for microarray and other high-throughput data, BMC Genomics, 12, 507, 10.1186/1471-2164-12-507 · DOI
- Kwak, 2013, Precise maps of RNA polymerase reveal how promoters direct initiation and pausing, Science, 339, 950, 10.1126/science.1229386 · DOI · Paper page
- Labun, 2019, CHOPCHOP v3: expanding the CRISPR web toolbox beyond genome editing, Nucleic Acids Res., 47, W171, 10.1093/nar/gkz365 · DOI
- Laitem, 2015, CDK9 inhibitors define elongation checkpoints at both ends of RNA polymerase II-transcribed genes, Nat. Struct. Mol. Biol., 22, 396, 10.1038/nsmb.3000 · DOI
- Langmead, 2012, Fast gapped-read alignment with Bowtie 2, Nat. Methods, 9, 357, 10.1038/nmeth.1923 · DOI · Paper page
- Lerdrup, 2016, An interactive environment for agile analysis and visualization of ChIP-sequencing data, Nat. Struct. Mol. Biol., 23, 349, 10.1038/nsmb.3180 · DOI
- Li, 2013, Kinetic competition between elongation rate and binding of NELF controls promoter-proximal pausing, Mol. Cell, 50, 711, 10.1016/j.molcel.2013.05.016 · DOI
- Lisabeth, 2019, Identification of Pirin as a molecular target of the CCG-1423/CCG-203971 series of antifibrotic and antimetastatic compounds, ACS Pharmacol. Transl. Sci., 2, 92, 10.1021/acsptsci.8b00048 · DOI
- Love, 2014, Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2, Genome Biol., 15, 550, 10.1186/s13059-014-0550-8 · DOI · Paper page
- Lundquist, 2014, Redox modification of nuclear actin by MICAL-2 regulates SRF signaling, Cell, 156, 563, 10.1016/j.cell.2013.12.035 · DOI
- Mahat, 2017, Use of conditioned media is critical for studies of regulation in response to rapid heat shock, Cell Stress Chaperones, 22, 155, 10.1007/s12192-016-0737-x · DOI
- Mahat, 2016, Mammalian heat shock response and mechanisms underlying its genome-wide transcriptional regulation, Mol. Cell, 62, 63, 10.1016/j.molcel.2016.02.025 · DOI · Paper page
- Mahat, 2016, Base-pair-resolution genome-wide mapping of active RNA polymerases using precision nuclear run-on (PRO-seq), Nat. Protoc., 11, 1455, 10.1038/nprot.2016.086 · DOI
- Mali, 2013, RNA-Guided Human Genome Engineering via Cas9, Science, 339, 823, 10.1126/science.1232033 · DOI · Paper page
- Martin, 2011, Cutadapt removes adapter sequences from high-throughput sequencing reads, EMBnet. J., 17, 3, 10.14806/ej.17.1.200 · DOI · Paper page
- Medjkane, 2009, Myocardin-related transcription factors and SRF are required for cytoskeletal dynamics and experimental metastasis, Nat. Cell Biol., 11, 257, 10.1038/ncb1833 · DOI
- Minami, 2012, Reciprocal expression of MRTF-A and myocardin is crucial for pathological vascular remodelling in mice, EMBO J., 31, 4428, 10.1038/emboj.2012.296 · DOI
- Miralles, 2003, Actin dynamics control SRF activity by regulation of its coactivator MAL, Cell, 113, 329, 10.1016/S0092-8674(03)00278-2 · DOI · Paper page
- Posern, 2006, Actin’ together: serum response factor, its cofactors and the link to signal transduction, Trends Cell Biol., 16, 588, 10.1016/j.tcb.2006.09.008 · DOI
- Rabenius, 2022, Quantifying RNA synthesis at rate-limiting steps of transcription using nascent RNA-sequencing data, STAR Protoc., 3, 101036, 10.1016/j.xpro.2021.101036 · DOI
- Ramirez, 2016, deepTools2: a next generation web server for deep-sequencing data analysis, Nucleic Acids Res., 44, W160, 10.1093/nar/gkw257 · DOI · Paper page
- Rawat, 2021, Stress-induced nuclear condensation of NELF drives transcriptional downregulation, Mol. Cell, 81, 1013, 10.1016/j.molcel.2021.01.016 · DOI
- Robinson, 2011, Integrative genomics viewer, Nat. Biotechnol., 29, 24, 10.1038/nbt.1754 · DOI · Paper page
- Salvany, 2014, The core and conserved role of MAL is homeostatic regulation of actin levels, Genes Dev., 28, 1048, 10.1101/gad.237743.114 · DOI
- Sidorenko, 2022, Lamina-associated polypeptide 2α is required for intranuclear MRTF-A activity, Sci. Rep., 12, 2306, 10.1038/s41598-022-06135-5 · DOI
- Sisson, 2015, Inhibition of myocardin-related transcription factor/serum response factor signaling decreases lung fibrosis and promotes mesenchymal cell apoptosis, Am. J. Pathol., 185, 969, 10.1016/j.ajpath.2014.12.005 · DOI
- Sokolova, 2018, Nuclear actin is required for transcription during Drosophila oogenesis, iScience, 9, 63, 10.1016/j.isci.2018.10.010 · DOI
- Somogyi, 2004, Evidence for tension-based regulation of Drosophila MAL and SRF during invasive cell migration, Dev. Cell, 7, 85, 10.1016/j.devcel.2004.05.020 · DOI
- Tellier, 2022, CDK9 and PP2A regulate RNA polymerase II transcription termination and coupled RNA maturation, EMBO Rep., 23, e54520, 10.15252/embr.202154520 · DOI
- Vartiainen, 2007, Nuclear actin regulates dynamic subcellular localization and activity of the SRF cofactor MAL, Science, 316, 1749, 10.1126/science.1141084 · DOI
- Vihervaara, 2018, Molecular mechanisms driving transcriptional stress responses, Nat. Rev. Genet., 19, 385, 10.1038/s41576-018-0001-6 · DOI
- Vihervaara, 2021, Stress-induced transcriptional memory accelerates promoter-proximal pause release and decelerates termination over mitotic divisions, Mol. Cell, 81, 1715, 10.1016/j.molcel.2021.03.007 · DOI
- Vilborg, 2017, Comparative analysis reveals genomic features of stress-induced transcriptional readthrough, Proc. Natl. Acad. Sci. USA, 114, E8362, 10.1073/pnas.1711120114 · DOI · Paper page
- Welch, 1985, Morphological study of the mammalian stress response: characterization of changes in cytoplasmic organelles, cytoskeleton, and nucleoli, and appearance of intranuclear actin filaments in rat fibroblasts after heat-shock treatment, J.Cell Biol., 101, 1198, 10.1083/jcb.101.4.1198 · DOI
- Wissink, 2019, Nascent RNA analyses: tracking transcription and its regulation, Nat. Rev. Genet., 20, 705, 10.1038/s41576-019-0159-6 · DOI
- Yu-Wai-Man, 2017, Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis, Sci. Rep., 7, 518, 10.1038/s41598-017-00212-w · DOI
- Zhang, 2022, LINC00891 regulated by miR-128-3p/GATA2 axis impedes lung cancer cell proliferation, invasion and EMT by inhibiting RhoA pathway, Acta Biochim. Biophys. Sin., 54, 378, 10.3724/abbs.2022005 · DOI
- Zhao, 2020, Serum response factor increases renal cell carcinoma migration and invasion through promoting epithelial-mesenchymal transition, Int. J. Urol., 27, 808, 10.1111/iju.14275 · DOI
Cited by
Sorted by citations
Torres‐Ortiz, B. S., Pérez‐Calixto, D., Carretero‐Ortega, J., Guzman‐López, A. G., Pinto‐Dueñas, D. C., Hernández‐Juárez, M., Jiménez‐Escobar, A., Rodríguez‐Hernández, A., Díaz‐Bello, B., Serna‐Márquez, N., et al. (2026) · The FEBS Journal · doi:10.1111/febs.70570
Metadata
- Authors
- Prajapati, B., Sokolova, M., Sidorenko, E., Kyriacou, M., Kyheröinen, S., Vihervaara, A., & Vartiainen, M. K.
- Affiliations
- University of Helsinki (FI)
- Science for Life Laboratory (SE)
- Corresponding author
- Vartiainen, Maria K.
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2024-07-01
- Volume
- 137
- Issue
- 13
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- OpenAlex
- W4399386461
- Cited by
- 6
- References
- 2
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3
- FWCI
- 0.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Cell Science (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- Funders
- Sigrid Juséliuksen Säätiö
- Jane ja Aatos Erkon Säätiö
- Research Council of Finland (338281, 324952, 330254)
- Veteskapsrådet (2021-02668)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- CCG-1423, MRTF, serum response factor, heat shock proteins, transcriptional inhibition, RNA polymerase II elongation, nascent transcription, small molecule inhibitors, actin cytoskeleton, heat shock response
- MeSH terms
- Animals, Heat-Shock Proteins, Humans, RNA, RNA Polymerase II, Transcription, Genetic, Trans-Activators, Serum Response Factor, Mice
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