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Disease activity drives divergent epigenetic and transcriptomic reprogramming of monocyte subpopulations in systemic lupus erythematosus
  1. Anna Guiomar Ferreté-Bonastre1,
  2. Mónica Martínez-Gallo2,
  3. Octavio Morante-Palacios3,
  4. Celia Lourdes Calvillo1,
  5. Josep Calafell-Segura1,
  6. Javier Rodríguez-Ubreva1,
  7. Manel Esteller4,5,6,7,
  8. Josefina Cortés-Hernández8,
  9. Esteban Ballestar1,9
  1. 1Epigenetics and Immune Disease Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Spain
  2. 2Immunology Division, Vall d'Hebron University Hospital and Diagnostic Immunology Research Group, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
  3. 3Early Oncology Data Science, Computational Biology, AstraZeneca, Barcelona, Spain
  4. 4Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Spain
  5. 5Centro de Investigación Biomédica en Red Cancer (CIBERONC), Madrid, Spain
  6. 6Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
  7. 7Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
  8. 8Rheumatology Department, Hospital Vall d'Hebron and Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
  9. 9Epigenetics in Inflammatory and Metabolic Diseases Laboratory, Health Science Center (HSC), East China Normal University (ECNU), Shanghai, China
  1. Correspondence to Dr Esteban Ballestar, Josep Carreras Research Institute, Badalona 08916, Spain; eballestar{at}carrerasresearch.org

Abstract

Objectives Systemic lupus erythematosus (SLE) is characterised by systemic inflammation involving various immune cell types. Monocytes, pivotal in promoting and regulating inflammation in SLE, differentiate from classic monocytes into intermediate and non-classic monocytes, assuming diverse roles and changing their proportions in inflammation. In this study, we investigated the epigenetic and transcriptomic profiles of these and novel monocyte subsets in SLE in relation to activity and progression.

Methods We obtained the DNA methylomes and transcriptomes of classic, intermediate, non-classic monocytes in patients with SLE (at first and follow-up visits) and healthy donors. We integrated these data with single-cell transcriptomics of SLE and healthy donors and interrogated their relationships with activity and progression.

Results In addition to shared DNA methylation and transcriptomic alterations associated with a strong interferon signature, we identified monocyte subset-specific alterations, especially in DNA methylation, which reflect an impact of SLE on monocyte differentiation. SLE classic monocytes exhibited a proinflammatory profile and were primed for macrophage differentiation. SLE non-classic monocytes displayed a T cell differentiation-related phenotype, with Th17-regulating features. Changes in monocyte proportions, DNA methylation and expression occurred in relation to disease activity and involved the STAT pathway. Integration of bulk with single-cell RNA sequencing datasets revealed disease activity-dependent expansion of SLE-specific monocyte subsets, further supported the interferon signature for classic monocytes, and associated intermediate and non-classic populations with exacerbated complement activation.

Conclusions Disease activity in SLE drives a subversion of the epigenome and transcriptome programme in monocyte differentiation, impacting the function of different subsets and allowing to generate predictive methods for activity and progression.

  • Lupus Erythematosus, Systemic
  • Autoimmune Diseases
  • Inflammation

Data availability statement

Data are available in a public, open access repository. Methylation array and Expression data for this publication have been deposited in NCBI’s Gene Expression Omnibus and are accessible through GEO SuperSeries with accession number GSE249641.

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Data availability statement

Data are available in a public, open access repository. Methylation array and Expression data for this publication have been deposited in NCBI’s Gene Expression Omnibus and are accessible through GEO SuperSeries with accession number GSE249641.

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Footnotes

  • Handling editor Josef S Smolen

  • Contributors AGF-B and EB conceived experiments. AGF-B performed experiments. AGF-B, OM-P, CLC, JC-S and JR-U performed biocomputing analysis. AGF-B performed statistical analysis. MM-G and JC-H performed patient selection and provided samples. AGF-B, ME and EB analysed the data. AGF-B illustrated graphical representations. AGF-B and EB wrote the paper. EB is the guarantor of the study. All authors read and approved the final manuscript.

  • Funding This study was funded by the Spanish Ministry of Science and Innovation (PID2020-117212RB-I00/AEI/10.13038). EB was funded by the Spanish Ministry of Science and Innovation (MICINN; grant numbers PID2020-117212RB-I00/AEI/10.13038/501100011033). MM-G was funded by Project PI18/00346 (Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.