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Histone modifications underlie monocyte dysregulation in patients with systemic sclerosis, underlining the treatment potential of epigenetic targeting
  1. Maarten van der Kroef1,2,
  2. Monica Castellucci3,
  3. Michal Mokry1,4,
  4. Marta Cossu1,2,
  5. Marianna Garonzi5,
  6. Lara M Bossini-Castillo6,7,
  7. Eleni Chouri1,2,
  8. Catharina G K Wichers1,2,
  9. Lorenzo Beretta8,
  10. Elena Trombetta9,
  11. Sandra Silva-Cardoso1,2,
  12. Nadia Vazirpanah1,2,
  13. Tiago Carvalheiro1,2,
  14. Chiara Angiolilli1,2,
  15. Cornelis P J Bekker1,2,
  16. Alsya J Affandi1,2,
  17. Kris A Reedquist1,2,
  18. Femke Bonte-Mineur10,
  19. Els J M Zirkzee10,
  20. Flavia Bazzoni3,
  21. Timothy R D J Radstake1,2,
  22. Marzia Rossato1,2,5
  1. 1 Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
  2. 2 Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
  3. 3 Division of General Pathology, Department of Medicine, University of Verona, Verona, Italy
  4. 4 Pediatric Gastroenterology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
  5. 5 Department of Biotechnology, University of Verona, Verona, Italy
  6. 6 Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Instituto de Parasitología y Biomedicina López-Neyra, PTS Granada, Granada, Spain
  7. 7 Department of cellular genetics, Wellcome Trust Sanger Institute, Cambridge, UK
  8. 8 Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy
  9. 9 Flow Cytometry Service, Analysis Laboratory, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy
  10. 10 Department of Rheumatology and Clinical Immunology, Maasstad Hospital, Rotterdam, The Netherlands
  1. Correspondence to Dr Timothy R D J Radstake, Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht 3584 CX, The Netherlands; T.R.D.J.Radstake{at}umcutrecht.nl

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.

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

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Footnotes

  • TRDJR and MR contributed equally.

  • Handling editor Josef S Smolen

  • Contributors MR designed and supervised the study. MvdK, MR, MCo and TRDJR wrote the manuscript. MvdK and MCo performed the experiments. MvdK, MR, MCo, MCa, EC, CGKW, LB, ET, SSC, NV, TC, CA, CPJB, FBM, EJMZ and AJA collected samples and analysed the data. MG, MM, LMBC, KAR and FB collected, analysed and supplied (clinical) data. All authors have critically revised the manuscript for important intellectual content.

  • Funding This work was funded by the Dutch Arthritis Foundation (Reuma Nederland) grant number NR14-3-403.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the board of the Local Medical Ethical Committee (METC).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement RNA-sequencing data presented in this study have been deposited in NCBI’s Gene Expression Omnibus (GEO) database under GEO: GSE124073 (Linked to GSE124075) The ChIP-seq data presented in this study have been deposited in NCBI’s Gene Expression Omnibus (GEO) database under GEO: GSE124070 (linked to GESE124075). Further data requests can be addressed to the corresponding author.

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