Transcriptional Derepression of CHD4/NuRD-regulated Genes in the Muscle of Patients with Dermatomyositis and anti-Mi2 Autoantibodies

Iago Pinal-Fernandez¹, Jose Cesar Milisenda², Katherine Pak¹, Sandra Muñoz-Braceras³, Maria Casal-Dominguez³, Jose Jiram Torres-Ruiz³, Stefania Dell´Orso⁴, Faiza Naz⁴, Gustavo Gutierrez-Cruz⁴, Yaiza Duque-Jaimez², Ana Matas-Garcia², Joan Padrosa⁵, Francesc J Garcia-Garcia², Mariona Guitart-Manpel², Gloria Garrabou², Ernesto Trallero-Araguas⁶, Brian Wallit⁷, Julie Paik⁸, Jemima Albayda⁸, Lisa Christopher-Stine⁸, Tom Lloyd⁹, Josep Maria Grau², Albert Selva-O’Callaghan⁶ and Andrew Mammen¹⁰, ¹National Institutes of Health, Bethesda, MD, ²Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain, ³Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, ⁴National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, ⁵CIBERER, Barcelona, Spain, Barcelona, Spain, ⁶Systemic Autoimmune Disease Unit, Vall d’Hebron Institute of Research, Barcelona, Spain, ⁷National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD, ⁸Johns Hopkins University, Baltimore, MD, ⁹Johns Hopkins University School of Medicine, Baltimore, MD, ¹⁰NIH, Bethesda, MD

Meeting: ACR Convergence 2023

Keywords: Bioinformatics, dermatomyositis, Myopathies, Myositis

Session Information

Date: Tuesday, November 14, 2023

Title: Abstracts: Muscle Biology, Myositis & Myopathies – Basic & Clinical Science I

Session Type: Abstract Session

Session Time: 2:00PM-3:30PM

Background/Purpose: Myositis is a heterogeneous family of diseases including dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM), antisynthetase syndrome (AS), and inclusion body myositis (IBM). Myositis-specific autoantibodies define different subtypes of myositis. For example, patients with anti-Mi2 autoantibodies targeting the CHD4/NuRD complex (a transcriptional repressor) have more severe muscle disease than other DM patients. This study aimed to define the transcriptional profile of muscle biopsies from anti-Mi2-positive DM patients.

Methods: RNA sequencing was performed on muscle biopsies (n=171) from patients with anti-Mi2-positive DM (n=18), DM without anti-Mi2 autoantibodies (n=32), AS (n=18), IMNM (n=54), and IBM (n=16) as well as 33 normal muscle biopsies. Genes specifically upregulated in anti-Mi2-positive DM were identified. Muscle biopsies were stained for human immunoglobulin and protein products corresponding to genes specifically upregulated in anti-Mi2-positive muscle biopsies.

Results: A set of 135 genes, including SCRT1 and MADCAM, was specifically overexpressed in anti-Mi2-positive DM muscle. This set was enriched for CHD4/NuRD-regulated genes and included genes that are not otherwise expressed in skeletal muscle. The expression levels of these genes correlated with anti-Mi2 autoantibody titers, markers of disease activity, and with the other members of the gene set. In anti-Mi2-positive muscle biopsies, immunoglobulin was localized to the nucleus, MADCAM protein was present in the cytoplasm of perifascicular fibers, and SCRT1 protein was localized to myofiber nuclei.

Conclusion: Based on these findings, we hypothesize that anti-Mi2 autoantibodies could exert a pathogenic effect by entering damaged myofibers, inhibiting the CHD4/NuRD complex, and subsequently derepressing the unique set of genes defined in this study.

Figure 1. The most differentially overexpressed genes in anti-Mi2 dermatomyositis muscle compared to all the other muscle biopsies included in the study (histologically normal muscle biopsies [NT], non-anti-Mi2 dermatomyositis [DM], antisynthetase syndrome [AS], immune-mediated necrotizing myositis [IMNM], and inclusion body myositis [IBM]).

Figure 2. Normalized expression (z-score) of the specifically overexpressed genes in patients with anti-Mi2-positive dermatomyositis (DM) compared with non-Mi2-positive DM.

Figure 3. Correlation of the most differentially specifically overexpressed genes in patients with anti-Mi2-positive dermatomyositis and: titer of anti-Mi2 autoantibodies by ELISA (Mi2t), type 1 interferon-inducible genes (ISG15, MX1), type 2 interferon-inducible genes (GBP2, IFI30), T-cell markers (CD3E, CD4, CD8), macrophages (CD14, CD68), markers of muscle differentiation (NCAM1, MYOG, PAX7, MYH3, MYH8), and structural mature muscle proteins (ACTA1, MYH1, MYH2).

Disclosures: I. Pinal-Fernandez: None; J. Milisenda: None; K. Pak: None; S. Muñoz-Braceras: None; M. Casal-Dominguez: None; J. Torres-Ruiz: None; S. Dell´Orso: None; F. Naz: None; G. Gutierrez-Cruz: None; Y. Duque-Jaimez: None; A. Matas-Garcia: None; J. Padrosa: None; F. Garcia-Garcia: None; M. Guitart-Manpel: None; G. Garrabou: None; E. Trallero-Araguas: None; B. Wallit: None; J. Paik: None; J. Albayda: Amgen, 5, Janssen, 5; L. Christopher-Stine: None; T. Lloyd: None; J. Grau: None; A. Selva-O’Callaghan: None; A. Mammen: None.

To cite this abstract in AMA style:

Pinal-Fernandez I, Milisenda J, Pak K, Muñoz-Braceras S, Casal-Dominguez M, Torres-Ruiz J, Dell´Orso S, Naz F, Gutierrez-Cruz G, Duque-Jaimez Y, Matas-Garcia A, Padrosa J, Garcia-Garcia F, Guitart-Manpel M, Garrabou G, Trallero-Araguas E, Wallit B, Paik J, Albayda J, Christopher-Stine L, Lloyd T, Grau J, Selva-O’Callaghan A, Mammen A. Transcriptional Derepression of CHD4/NuRD-regulated Genes in the Muscle of Patients with Dermatomyositis and anti-Mi2 Autoantibodies [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/transcriptional-derepression-of-chd4-nurd-regulated-genes-in-the-muscle-of-patients-with-dermatomyositis-and-anti-mi2-autoantibodies/. Accessed .

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