Histone modifications underlie monocyte dysregulation in patients with systemic sclerosis, underlining the treatment potential of epigenetic targeting

Maarten Van Der Kroef, Monica Castellucci, Michal Mokry, Marta Cossu, Marianna Garonzi, Lara M. Bossini-Castillo, Eleni Chouri, Catharina G.K. Wichers, Lorenzo Beretta, Elena Trombetta, Sandra Silva-Cardoso, Nadia Vazirpanah, Tiago Carvalheiro, Chiara Angiolilli, Cornelis P.J. Bekker, Alsya J. Affandi, Kris A. Reedquist, Femke Bonte-Mineur, Els J.M. Zirkzee, Flavia BazzoniTimothy R.D.J. Radstake, Marzia Rossato

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background and objective Systemic sclerosis (SSc) is a severe autoimmune disease, in which the pathogenesis is dependent on both genetic and epigenetic factors. Altered gene expression in SSc monocytes, particularly of interferon (IFN)-responsive genes, suggests their involvement in SSc development. We investigated the correlation between epigenetic histone marks and gene expression in SSc monocytes. Methods Chromatin immunoprecipitation followed by sequencing (ChIPseq) for histone marks H3K4me3 and H3K27ac was performed on monocytes of nine healthy controls and 14 patients with SSc. RNA sequencing was performed in parallel to identify aberrantly expressed genes and their correlation with the levels of H3K4me3 and H3K27ac located nearby their transcription start sites. ChIP-qPCR assays were used to verify the role of bromodomain proteins, H3K27ac and STATs on IFN-responsive gene expression. Results 1046 and 534 genomic loci showed aberrant H3K4me3 and H3K27ac marks, respectively, in SSc monocytes. The expression of 381 genes was directly and significantly proportional to the levels of such chromatin marks present near their transcription start site. Genes correlated to altered histone marks were enriched for immune, IFN and antiviral pathways and presented with recurrent binding sites for IRF and STAT transcription factors at their promoters. IFNα induced the binding of STAT1 and STAT2 at the promoter of two of these genes, while blocking acetylation readers using the bromodomain BET family inhibitor JQ1 suppressed their expression. Conclusion SSc monocytes have altered chromatin marks correlating with their IFN signature. Enzymes modulating these reversible marks may provide interesting therapeutic targets to restore monocyte homeostasis to treat or even prevent SSc.

Original languageEnglish
Pages (from-to)529-538
Number of pages10
JournalAnnals of the Rheumatic Diseases
Volume78
Issue number4
DOIs
Publication statusPublished - Apr 1 2019

Fingerprint

Histone Code
Systemic Scleroderma
Epigenomics
Histones
Monocytes
Genes
Interferons
Gene expression
Chromatin
Transcription Initiation Site
Gene Expression
Interferon Regulatory Factors
STAT Transcription Factors
Therapeutics
Acetylation
Interferon-gamma
Antiviral Agents
Assays
RNA Sequence Analysis
Binding Sites

Keywords

  • epigenetic targeting
  • epigenetics
  • histone modification
  • monocytes
  • systemic sclerosis

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Histone modifications underlie monocyte dysregulation in patients with systemic sclerosis, underlining the treatment potential of epigenetic targeting. / Van Der Kroef, Maarten; Castellucci, Monica; Mokry, Michal; Cossu, Marta; Garonzi, Marianna; Bossini-Castillo, Lara M.; Chouri, Eleni; Wichers, Catharina G.K.; Beretta, Lorenzo; Trombetta, Elena; Silva-Cardoso, Sandra; Vazirpanah, Nadia; Carvalheiro, Tiago; Angiolilli, Chiara; Bekker, Cornelis P.J.; Affandi, Alsya J.; Reedquist, Kris A.; Bonte-Mineur, Femke; Zirkzee, Els J.M.; Bazzoni, Flavia; Radstake, Timothy R.D.J.; Rossato, Marzia.

In: Annals of the Rheumatic Diseases, Vol. 78, No. 4, 01.04.2019, p. 529-538.

Research output: Contribution to journalArticle

Van Der Kroef, M, Castellucci, M, Mokry, M, Cossu, M, Garonzi, M, Bossini-Castillo, LM, Chouri, E, Wichers, CGK, Beretta, L, Trombetta, E, Silva-Cardoso, S, Vazirpanah, N, Carvalheiro, T, Angiolilli, C, Bekker, CPJ, Affandi, AJ, Reedquist, KA, Bonte-Mineur, F, Zirkzee, EJM, Bazzoni, F, Radstake, TRDJ & Rossato, M 2019, 'Histone modifications underlie monocyte dysregulation in patients with systemic sclerosis, underlining the treatment potential of epigenetic targeting', Annals of the Rheumatic Diseases, vol. 78, no. 4, pp. 529-538. https://doi.org/10.1136/annrheumdis-2018-214295
Van Der Kroef, Maarten ; Castellucci, Monica ; Mokry, Michal ; Cossu, Marta ; Garonzi, Marianna ; Bossini-Castillo, Lara M. ; Chouri, Eleni ; Wichers, Catharina G.K. ; Beretta, Lorenzo ; Trombetta, Elena ; Silva-Cardoso, Sandra ; Vazirpanah, Nadia ; Carvalheiro, Tiago ; Angiolilli, Chiara ; Bekker, Cornelis P.J. ; Affandi, Alsya J. ; Reedquist, Kris A. ; Bonte-Mineur, Femke ; Zirkzee, Els J.M. ; Bazzoni, Flavia ; Radstake, Timothy R.D.J. ; Rossato, Marzia. / Histone modifications underlie monocyte dysregulation in patients with systemic sclerosis, underlining the treatment potential of epigenetic targeting. In: Annals of the Rheumatic Diseases. 2019 ; Vol. 78, No. 4. pp. 529-538.
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abstract = "Background and objective Systemic sclerosis (SSc) is a severe autoimmune disease, in which the pathogenesis is dependent on both genetic and epigenetic factors. Altered gene expression in SSc monocytes, particularly of interferon (IFN)-responsive genes, suggests their involvement in SSc development. We investigated the correlation between epigenetic histone marks and gene expression in SSc monocytes. Methods Chromatin immunoprecipitation followed by sequencing (ChIPseq) for histone marks H3K4me3 and H3K27ac was performed on monocytes of nine healthy controls and 14 patients with SSc. RNA sequencing was performed in parallel to identify aberrantly expressed genes and their correlation with the levels of H3K4me3 and H3K27ac located nearby their transcription start sites. ChIP-qPCR assays were used to verify the role of bromodomain proteins, H3K27ac and STATs on IFN-responsive gene expression. Results 1046 and 534 genomic loci showed aberrant H3K4me3 and H3K27ac marks, respectively, in SSc monocytes. The expression of 381 genes was directly and significantly proportional to the levels of such chromatin marks present near their transcription start site. Genes correlated to altered histone marks were enriched for immune, IFN and antiviral pathways and presented with recurrent binding sites for IRF and STAT transcription factors at their promoters. IFNα induced the binding of STAT1 and STAT2 at the promoter of two of these genes, while blocking acetylation readers using the bromodomain BET family inhibitor JQ1 suppressed their expression. Conclusion SSc monocytes have altered chromatin marks correlating with their IFN signature. Enzymes modulating these reversible marks may provide interesting therapeutic targets to restore monocyte homeostasis to treat or even prevent SSc.",
keywords = "epigenetic targeting, epigenetics, histone modification, monocytes, systemic sclerosis",
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T1 - Histone modifications underlie monocyte dysregulation in patients with systemic sclerosis, underlining the treatment potential of epigenetic targeting

AU - Van Der Kroef, Maarten

AU - Castellucci, Monica

AU - Mokry, Michal

AU - Cossu, Marta

AU - Garonzi, Marianna

AU - Bossini-Castillo, Lara M.

AU - Chouri, Eleni

AU - Wichers, Catharina G.K.

AU - Beretta, Lorenzo

AU - Trombetta, Elena

AU - Silva-Cardoso, Sandra

AU - Vazirpanah, Nadia

AU - Carvalheiro, Tiago

AU - Angiolilli, Chiara

AU - Bekker, Cornelis P.J.

AU - Affandi, Alsya J.

AU - Reedquist, Kris A.

AU - Bonte-Mineur, Femke

AU - Zirkzee, Els J.M.

AU - Bazzoni, Flavia

AU - Radstake, Timothy R.D.J.

AU - Rossato, Marzia

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Background and objective Systemic sclerosis (SSc) is a severe autoimmune disease, in which the pathogenesis is dependent on both genetic and epigenetic factors. Altered gene expression in SSc monocytes, particularly of interferon (IFN)-responsive genes, suggests their involvement in SSc development. We investigated the correlation between epigenetic histone marks and gene expression in SSc monocytes. Methods Chromatin immunoprecipitation followed by sequencing (ChIPseq) for histone marks H3K4me3 and H3K27ac was performed on monocytes of nine healthy controls and 14 patients with SSc. RNA sequencing was performed in parallel to identify aberrantly expressed genes and their correlation with the levels of H3K4me3 and H3K27ac located nearby their transcription start sites. ChIP-qPCR assays were used to verify the role of bromodomain proteins, H3K27ac and STATs on IFN-responsive gene expression. Results 1046 and 534 genomic loci showed aberrant H3K4me3 and H3K27ac marks, respectively, in SSc monocytes. The expression of 381 genes was directly and significantly proportional to the levels of such chromatin marks present near their transcription start site. Genes correlated to altered histone marks were enriched for immune, IFN and antiviral pathways and presented with recurrent binding sites for IRF and STAT transcription factors at their promoters. IFNα induced the binding of STAT1 and STAT2 at the promoter of two of these genes, while blocking acetylation readers using the bromodomain BET family inhibitor JQ1 suppressed their expression. Conclusion SSc monocytes have altered chromatin marks correlating with their IFN signature. Enzymes modulating these reversible marks may provide interesting therapeutic targets to restore monocyte homeostasis to treat or even prevent SSc.

AB - Background and objective Systemic sclerosis (SSc) is a severe autoimmune disease, in which the pathogenesis is dependent on both genetic and epigenetic factors. Altered gene expression in SSc monocytes, particularly of interferon (IFN)-responsive genes, suggests their involvement in SSc development. We investigated the correlation between epigenetic histone marks and gene expression in SSc monocytes. Methods Chromatin immunoprecipitation followed by sequencing (ChIPseq) for histone marks H3K4me3 and H3K27ac was performed on monocytes of nine healthy controls and 14 patients with SSc. RNA sequencing was performed in parallel to identify aberrantly expressed genes and their correlation with the levels of H3K4me3 and H3K27ac located nearby their transcription start sites. ChIP-qPCR assays were used to verify the role of bromodomain proteins, H3K27ac and STATs on IFN-responsive gene expression. Results 1046 and 534 genomic loci showed aberrant H3K4me3 and H3K27ac marks, respectively, in SSc monocytes. The expression of 381 genes was directly and significantly proportional to the levels of such chromatin marks present near their transcription start site. Genes correlated to altered histone marks were enriched for immune, IFN and antiviral pathways and presented with recurrent binding sites for IRF and STAT transcription factors at their promoters. IFNα induced the binding of STAT1 and STAT2 at the promoter of two of these genes, while blocking acetylation readers using the bromodomain BET family inhibitor JQ1 suppressed their expression. Conclusion SSc monocytes have altered chromatin marks correlating with their IFN signature. Enzymes modulating these reversible marks may provide interesting therapeutic targets to restore monocyte homeostasis to treat or even prevent SSc.

KW - epigenetic targeting

KW - epigenetics

KW - histone modification

KW - monocytes

KW - systemic sclerosis

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