TY - JOUR
T1 - Transcriptional derepression of CHD4/NuRD-regulated genes in the muscle of patients with dermatomyositis and anti-Mi2 autoantibodies
AU - Pinal-Fernandez, Iago
AU - Milisenda, Jose Cesar
AU - Pak, Katherine
AU - Muñoz-Braceras, Sandra
AU - Casal-Dominguez, Maria
AU - Torres-Ruiz, Jiram
AU - Dell'orso, Stefania
AU - Naz, Faiza
AU - Gutierrez-Cruz, Gustavo
AU - Duque-Jaimez, Yaiza
AU - Matas-Garcia, Ana
AU - Padrosa, Joan
AU - Garcia-Garcia, Francesc J.
AU - Guitart-Mampel, Mariona
AU - Garrabou, Gloria
AU - Trallero-Araguás, Ernesto
AU - Walitt, Brian
AU - Paik, Julie J.
AU - Albayda, Jemima
AU - Christopher-Stine, Lisa
AU - Lloyd, Thomas E.
AU - Grau-Junyent, Josep Maria
AU - Selva-O'callaghan, Albert
AU - Mammen, Andrew Lee
N1 - Publisher Copyright:
© 2023 Authors. All rights reserved.
PY - 2023/8/1
Y1 - 2023/8/1
N2 - Objectives Myositis is a heterogeneous family of diseases including dermatomyositis (DM), immune-mediated necrotising 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 chromodomain helicase DNA-binding protein 4 (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 MADCAM1, 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 titres, markers of disease activity and with the other members of the gene set. In anti-Mi2-positive muscle biopsies, immunoglobulin was localised to the myonuclei, MAdCAM-1 protein was present in the cytoplasm of perifascicular fibres, and SCRT1 protein was localised to myofibre nuclei. Conclusions Based on these findings, we hypothesise that anti-Mi2 autoantibodies could exert a pathogenic effect by entering damaged myofibres, inhibiting the CHD4/NuRD complex, and subsequently derepressing the unique set of genes defined in this study.
AB - Objectives Myositis is a heterogeneous family of diseases including dermatomyositis (DM), immune-mediated necrotising 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 chromodomain helicase DNA-binding protein 4 (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 MADCAM1, 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 titres, markers of disease activity and with the other members of the gene set. In anti-Mi2-positive muscle biopsies, immunoglobulin was localised to the myonuclei, MAdCAM-1 protein was present in the cytoplasm of perifascicular fibres, and SCRT1 protein was localised to myofibre nuclei. Conclusions Based on these findings, we hypothesise that anti-Mi2 autoantibodies could exert a pathogenic effect by entering damaged myofibres, inhibiting the CHD4/NuRD complex, and subsequently derepressing the unique set of genes defined in this study.
KW - autoimmunity
KW - dermatomyositis
KW - inflammation
KW - polymyositis
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U2 - 10.1136/ard-2023-223873
DO - 10.1136/ard-2023-223873
M3 - Article
C2 - 37130727
AN - SCOPUS:85160231842
SN - 0003-4967
VL - 82
SP - 1091
EP - 1097
JO - Annals of the rheumatic diseases
JF - Annals of the rheumatic diseases
IS - 8
ER -