Inhibition of H3K27 histone trimethylation activates fibroblasts and induces fibrosis
Open accessAbstract
Objectives Epigenetic modifications such as DNA methylation and histone acetylation have been implicated in the pathogenesis of systemic sclerosis. However, histone methylation has not been investigated so far. We therefore aimed to evaluate the role of the trimethylation of histone H3 on lysine 27 (H3K27me3) on fibroblast activation and fibrosis. Methods H3K27me3 was inhibited by 3-deazaneplanocin A (DZNep) in cultured fibroblasts and in two murine models of dermal fibrosis. Fibrosis was analysed by assessment of the dermal thickening, determination of the hydroxyproline content and by quantification of the numbers of myofibroblasts. The expression of fos-related antigen 2 (fra-2) was assessed by real-time PCR, western blot and immunohistochemistry and modulated by siRNA. Results Inhibition of H3K27me3 stimulated the release of collagen in cultured fibroblasts in a time and dose-dependent manner. Treatment with DZNep exacerbated fibrosis induced by bleomycin or by overexpression of a constitutively active transforming growth factor β receptor type I. Moreover, treatment with DZNep alone was sufficient to induce fibrosis. Inhibition of H3K27me3 induced the expression of the profibrotic transcription factor fra-2 in vitro and in vivo. Knockdown of fra-2 completely prevented the profibrotic effects of DZNep. Conclusions These data demonstrate a novel role of H3 Lys27 histone methylation in fibrosis. In contrast to other epigenetic modifications such as DNA methylation and histone acetylation, H3 Lys27 histone methylation acts as a negative regulator of fibroblast activation in vitro and in vivo by repressing the expression of fra-2.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Pharmacological inhibition of H3K27 trimethylation induces skin fibrosis and aggravates pathology in bleomycin induced skin fibrosis.
“Furthermore, pharmacological inhibition of H3K27 trimethylation induces skin fibrosis and aggravates pathology in bleomcyin induced skin fibrosis (100).”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [100]
JMJD3 removes the H3K27me3 mark from histones, and this mark can repress expression of pro-fibrotic genes such as collagen type I in fibroblasts.
“This histone demethylase removes the so-called H3K27me3 mark from histones, and this mark can repress expression of pro-fibrotic genes such as collagen type I in fibroblasts (100).”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [100]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Woessner, J. F. (1961) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(61)90291-0 · Cited by 3,851 · see citing works
Gabrielli, A., Avvedimento, E. V., & Krieg, T. M. (2009) · New England Journal of Medicine · doi:10.1056/nejmra0806188 · Cited by 1,388 · see citing works
Systemic sclerosis: a prototypic multisystem fibrotic disorder
Varga, J., & Abraham, D. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31139 · Cited by 1,164 · see citing works
Miranda, T. B., Cortez, C. C., Yoo, C. B., Liang, G., Abe, M., Kelly, T. K., Márquez, V. E., & Jones, P. A. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-0013 · Cited by 588 · see citing works
Reversal of Histone Methylation: Biochemical and Molecular Mechanisms of Histone Demethylases
Mosammaparast, N., & Shi, Y. (2010) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.78.070907.103946 · Cited by 585 · see citing works
MicroRNA‐29, a key regulator of collagen expression in systemic sclerosis
Maurer, B., Stańczyk, J., Jüngel, A., Akhmetshina, A., Trenkmann, M., Brock, M., Kowal‐Bielecka, O., Gay, R. E., Michel, B. A., Distler, J. H. W., et al. (2010) · Arthritis & Rheumatism · doi:10.1002/art.27443 · Cited by 536 · see citing works
Self-citationWang, Y., Fan, P., & Kahaleh, B. (2006) · Arthritis & Rheumatism · doi:10.1002/art.21948 · Cited by 347 · see citing works
Distler, J. H. W., Jüngel, A., Huber, L. C., Seemayer, C. A., Reich, C. F., Gay, R. E., Michel, B. A., Fontana, A., Gay, S., Pisetsky, D. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409781102 · Cited by 328 · see citing works
Self-citationPlatelet-derived serotonin links vascular disease and tissue fibrosis
Dees, C., Akhmetshina, A., Zerr, P., Reich, N., Palumbo, K., Horn, A., Jüngel, A., Beyer, C., Krönke, G., Zwerina, J., et al. (2011) · Journal of Experimental Medicine · doi:10.1084/jem.20101629 · Cited by 266 · see citing works
Self-citationEpigenetic Histone Methylation Modulates Fibrotic Gene Expression
Sun, G., Reddy, M. A., Yuan, H., Lanting, L. L., Kato, M. V., & Natarajan, R. D. (2010) · Journal of the American Society of Nephrology · doi:10.1681/asn.2010060633 · Cited by 238 · see citing works
Histone Modifications and Cancer
Sawan, C., & Herceg, Z. (2010) · Advances in genetics · doi:10.1016/b978-0-12-380866-0.60003-4 · Cited by 230 · see citing works
Akhmetshina, A., Venalis, P., Dees, C., Busch, N., Zwerina, J., Schett, G. A., Distler, O., & Distler, J. H. W. (2008) · Arthritis & Rheumatism · doi:10.1002/art.24186 · Cited by 212 · see citing works
Self-citationDevelopment of pulmonary fibrosis through a pathway involving the transcription factor Fra-2/AP-1
Eferl, R., Hasselblatt, P., Rath, M., Popper, H., Zenz, R., Komnenovic, V., Idarraga, M. H., Kenner, L., & Wagner, E. F. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0801414105 · Cited by 207 · see citing works
Akhmetshina, A., Dees, C., Pileckyte, M., Maurer, B., Axmann, R., Jüngel, A., Zwerina, J., Gay, S., Schett, G., Distler, O., et al. (2008) · The FASEB Journal · doi:10.1096/fj.07-105627 · Cited by 187 · see citing works
Self-citationHuber, L. C., Distler, J. H. W., Moritz, F., Hemmatazad, H., Hauser, T., Michel, B. A., Gay, R. E., Matucci‐Cerinic, M., Gay, S., Distler, O., et al. (2007) · Arthritis & Rheumatism · doi:10.1002/art.22759 · Cited by 165 · see citing works
Self-citationNotch signalling regulates fibroblast activation and collagen release in systemic sclerosis
Dees, C., Tomčík, M., Zerr, P., Akhmetshina, A., Horn, A., Palumbo, K., Beyer, C., Zwerina, J., Distler, O., Schett, G. A., et al. (2011) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2010.134742 · Cited by 158 · see citing works
Self-citationAnimal models of systemic sclerosis: Prospects and limitations
Beyer, C., Schett, G. A., Distler, O., & Distler, J. H. W. (2010) · Arthritis & Rheumatism · doi:10.1002/art.27647 · Cited by 154 · see citing works
Self-citationExpression of interleukin‐21 receptor in epidermis from patients with systemic sclerosis
Distler, J. H. W., Jüngel, A., Kowal‐Bielecka, O., Michel, B. A., Gay, R. E., Sprott, H., Matucci‐Cerinic, M., Chilla, M., Reich, K., Kalden, J. R., et al. (2005) · Arthritis & Rheumatism · doi:10.1002/art.20883 · Cited by 141 · see citing works
Self-citationMaurer, B., Busch, N., Jüngel, A., Pileckytė, M., Gay, R. E., Michel, B. A., Schett, G. A., Gay, S., Distler, J. H. W., & Distler, O. (2009) · Circulation · doi:10.1161/circulationaha.109.855114 · Cited by 126 · see citing works
Self-citationAkhmetshina, A., Dees, C., Pileckytė, M., Szűcs, G., Spriewald, B. M., Zwerina, J., Distler, O., Schett, G. A., & Distler, J. H. W. (2008) · Arthritis & Rheumatism · doi:10.1002/art.23677 · Cited by 121 · see citing works
Self-citationHistone deacetylase 7, a potential target for the antifibrotic treatment of systemic sclerosis
Hemmatazad, H., Maciejewska-Rodrigues, H., Maurer, B., Brentano, F., Pileckytė, M., Distler, J. H. W., Gay, R. E., Michel, B. A., Gay, S., Huber, L. C., et al. (2009) · Arthritis & Rheumatism · doi:10.1002/art.24494 · Cited by 113 · see citing works
Self-citationReich, N., Maurer, B., Akhmetshina, A., Venalis, P., Dees, C., Zerr, P., Palumbo, K., Zwerina, J., Nevskaya, T., Gay, S., et al. (2010) · Arthritis & Rheumatism · doi:10.1002/art.25056 · Cited by 112 · see citing works
Self-citationCoward, W. R., Watts, K., Feghali‐Bostwick, C. A., Jenkins, G. R., & Pang, L. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.01527-09 · Cited by 103 · see citing works
Avouac, J., Palumbo, K., Tomčík, M., Zerr, P., Dees, C., Horn, A., Maurer, B., Akhmetshina, A., Beyer, C., Sadowski, A., et al. (2011) · Arthritis & Rheumatism · doi:10.1002/art.33501 · Cited by 96 · see citing works
Self-citationDistler, J. H. W., Jüngel, A., Caretto, D., Schulze-Horsel, U., Kowal‐Bielecka, O., Gay, R. E., Michel, B. A., Müller‐Ladner, U., Kalden, J. R., Gay, S., et al. (2005) · Arthritis & Rheumatism · doi:10.1002/art.21497 · Cited by 92 · see citing works
Self-citationPolycomb genes and cancer: Time for clinical application?
Crea, F., Paolicchi, E., Márquez, V. E., & Danesi, R. (2011) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2011.10.007 · Cited by 84 · see citing works
Glazer, R. I., Knode, M. C., Tseng, C. K. H., et al. (1986) · Biochemical Pharmacology · doi:10.1016/0006-2952(86)90774-4 · Cited by 77 · see citing works
Palumbo, K., Zerr, P., Tomčík, M., Vollath, S., Dees, C., Akhmetshina, A., Avouac, J., Yaniv, M., Distler, O., Schett, G. A., et al. (2011) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2010.148296 · Cited by 70 · see citing works
Self-citationHe, S., Wang, J., Kato, K., Xie, F., Varambally, S., Mineishi, S., Kuick, R. D., Mochizuki, K., Liu, Y., Nieves, E. C., et al. (2011) · Blood · doi:10.1182/blood-2011-06-364422 · Cited by 68 · see citing works
An Introduction to Epigenetics
Ballestar, E. (2011) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-8216-2_1 · Cited by 66 · see citing works
Epigenetics in inflammatory rheumatic diseases
Huber, L. C., Stańczyk, J., Jüngel, A., & Gay, S. (2007) · Arthritis & Rheumatism · doi:10.1002/art.22948 · Cited by 56 · see citing works
Epigenetic modifications: novel therapeutic strategies for systemic sclerosis?
Jüngel, A., Distler, J. H. W., Gay, S., & Distler, O. (2011) · Expert Review of Clinical Immunology · doi:10.1586/eci.11.37 · Cited by 29 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 3
- Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med 2009; 360:1989-2003.
- Avouac J, Palumbo K, Tomcik M, et al. Inhibition of AP-1 signaling abrogates TGF-ss mediated activation of fibroblasts and prevents experimental fibrosis. Arthritis Rheum 2012;64:1642-52.
- Dees C, Akhmetshina A, Busch N, et al. TGFβ stimulates promoter hypermethylation and subsequent silencing of the anti-fibrotic gene socs-3. Arthritis Rheum 2009;60:S474.
Cited by
Sorted by citations
Unraveling SSc Pathophysiology; The Myofibroblast
van Caam, A., Vonk, M., van den Hoogen, F., van Lent, P., & van der Kraan, P. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02452 · Cited by 153 · see citing works
Bergmann, C., Brandt, A., Merlevede, B., Hallenberger, L., Dees, C., Wohlfahrt, T., Pötter, S., Zhang, Y., Chen, C.-W., Mallano, T., et al. (2018) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2017-211501 · Cited by 62 · see citing works
Self-citation
- Authors
- Krämer, M., Dees, C., Huang, J., Schlottmann, I., Palumbo-Zerr, K., Zerr, P., Gelse, K., Beyer, C., Distler, A., Marquez, V. E., Distler, O., Schett, G., & Distler, J. H. W.
- Affiliations
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University Hospital Zurich (CH)
- Corresponding author
- Distler, Jörg H W
- Venue
- Annals of the Rheumatic Diseases
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 72
- Issue
- 4
- Pages
- 614-620
- ISSN
- 0003-4967 (ISSN-L)
- OpenAlex
- W2149312319
- Cited by
- 109
- References
- 32
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 7 · 2023: 6 · 2022: 8 · 2021: 8 · 2020: 5 · 2019: 9 · 2018: 11 · 2017: 8 · 2016: 12 · 2015: 9 · 2014: 14 · 2013: 5
- FWCI
- 6.45
- Type
- journal article
- Language
- en
- Open access
- green
- nbn-resolving.org
- Licence
- Locations
- Annals of the Rheumatic Diseases (publishedVersion)
- PubMed (publishedVersion)
- OPUS FAU (Kooperativer Bibliotheksverbund Berlin-Brandenburg (KOBV), on behalf of the Universitätsbibliothek Erlangen-Nürnberg) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
- Health Sciences › Medicine › Rheumatology › Dupuytren's Contracture and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- H3K27me3, histone methylation, systemic sclerosis, skin fibrosis, fibroblast activation, DZNep, Fra-2, epigenetic regulation, myofibroblasts, bleomycin-induced fibrosis, TGF-beta type I receptor, histone demethylase inhibition
- MeSH terms
- Adult, Animals, Antibiotics, Antineoplastic, Bleomycin, Cells, Cultured, Collagen, Disease Models, Animal, Enzyme Inhibitors, Fibroblasts, Fibrosis, Histones, Humans, Male, Mice, Inbred DBA, Middle Aged, DNA Methylation, Dermis, Epigenesis, Genetic, Scleroderma, Diffuse, Mice, Fos-Related Antigen-2, Young Adult, Jumonji Domain-Containing Histone Demethylases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
