Genetic association between methyl-CpG binding protein 2 (MECP2) and primary Sjogren's syndrome

Cobb, Beth L.; Fei, Yiping; Jönsson, Roland; Bolstad, Anne Isine; Brun, Johan G.; Rischmueller, Maureen; Lester, Susan; Witte, Torsten; Illei, Gabor G.; Brennan, Michael T.; Bowman, Simon; Moser, Kathy L.; Harley, John B.; Sawalha, Amr H.

doi:10.1136/ard.2009.122903

Cited by 32 publications

(28 citation statements)

References 10 publications

(10 reference statements)

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“…RTT is a devastating disorder that afflicts 1 in 10,000 females and whose symptoms are largely neurodevelopmental (11). Based on the limited immunological studies on RTT patients, however, hints of immunological abnormalities have gradually emerged: Polymorphisms within the human mecp2 locus have recently been associated with an increased susceptibility to systemic lupus erythematosus (12,13) and primary Sjögren's syndrome (14), suggesting that mecp2 gene mutations may also contribute to the pathogenesis of inflammatory diseases, and a cohort study also demonstrated significantly elevated levels of IgG against food proteins in the sera of RTT patients (15), which may reflect the possibility of gut inflammation or breakdown of the intestinal barrier; most intriguingly, the transplantation of wild-type (WT) bone marrow successfully arrested RTT disease in MeCP2-null mice (16). Nevertheless, apart from these correlative studies, MeCP2's causative role in immune regulation remains largely unexplored.…”

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confidence: 99%

MeCP2 enforces Foxp3 expression to promote regulatory T cells’ resilience to inflammation

Jiang

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Forkhead box P3 + (Foxp3 + ) regulatory T cells (Tregs) are important for maintaining immune homeostasis and tolerance. The pivotal role of Tregs in immune tolerance demands that they possess a dedicated molecular machinery to maintain stable Foxp3 expression when challenged by an inflammatory environment. Whereas epigenetic mechanisms acting on the foxp3 locus have been extensively implicated in Tregs’ stable expression of Foxp3, the detailed molecular machinery remains elusive. In this study, we show that methyl-CpG binding protein 2 (MeCP2), an X-linked multifunctional epigenetic regulator, is a crucial player in the epigenetic machinery that confers Tregs with resilience against inflammation. Our study provides, to our knowledge, the first mechanistic description by which MeCP2, a molecule best known for its function in the central nervous system, regulates Treg function and immune tolerance.

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mentioning

confidence: 99%

MeCP2 enforces Foxp3 expression to promote regulatory T cells’ resilience to inflammation

Jiang

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Section: Discussionmentioning

confidence: 99%

“…Links between genetic and epigenetic factors have recently been observed in circulating T lymphocytes (38). In particular, a polymorphism in the methyl-CpGbinding protein 2 (MECP-2) gene appeared to be associated with primary SS (38). MECP-2 is a transcriptional repressor that binds to methylated CpG dinucleotides, resulting in tighter winding of the chromatin coil and reduced transcription (37).…”

Section: Discussionmentioning

confidence: 99%

Alterations in type I hemidesmosome components suggestive of epigenetic control in the salivary glands of patients with Sjögren's syndrome

González

Aguilera

Alliende

et al. 2011

Arthritis & Rheumatism

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Objective. Acinar cells in the salivary glands of patients with Sjögren's syndrome (SS) display severe alterations in anchorage to the basal lamina. Bioinformatics analysis of the BP230 gene sequence has revealed the presence of CpG islands that might be involved in epigenetic control of gene expression, and methylation of the BP230 promotor region may be implicated as an epigenetic control mechanism in salivary gland damage. Thus, the present study was undertaken to evaluate the protein BP230, as well as proteins BP180, ␣6␤4 integrin, and cytokeratin-18, for their expression levels, localization, and ability to form hemidesmosome adhesion complexes.Methods. Eighteen patients with primary SS and 14 healthy control subjects were studied. Levels of messenger RNA (mRNA) and protein were measured by reverse transcription-polymerase chain reaction and Western blotting, respectively. BP230 methylation was determined by methylation-sensitive polymerase chain reaction. Protein complexes were analyzed by immunoprecipitation and assessed for localization by immunofluorescence.Results. In patients with SS as compared with controls, BP230 mRNA levels were decreased while protein levels were increased, and the gene promotor region was hypermethylated. Augmented proteolysis of BP180 was detected, since levels of linear IgA disease fragment 1 were increased. The complex-forming ability of BP230, BP180, ␣6␤4 integrin, and cytokeratin-18 was maintained in patients with SS, in contrast to that in controls. BP230 and BP180 colocalized at the basal membrane of acinar cells, and cleavage of BP180 coincided with a loss of colocalization.Conclusion. The decrease in BP230 mRNA levels may be explained by gene hypermethylation. We postulate that local epigenetic modifications of BP230 are produced in response to factors present in the damaged salivary glands of patients with SS. Additionally, the paradoxical increase in BP230 protein levels and the formation of both normal and altered adhesion complexes may help avoid cell death induced by the loss of anchorage.Severe alterations in acinar cells and the extracellular matrix (ECM) are recurrent observations in the labial salivary glands (LSGs) of patients with primary Sjögren's syndrome (SS) (1-4). LSG epithelial cells are linked to the basal lamina (BL) through several transmembrane protein complexes that have important functions in adhesion and cell signaling (5). These adhesion complexes include ␣6␤1 and ␣6␤4 integrins as a central

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“…STAT4 polymorphism was also associated with SS (Nordmark et al, 2009;Korman et al, 2008;Gestermann et al, 2010;Palomino-Morales et al, 2010). MECP2 and IL2-IL21 polymorphisms have also been associated with SS (Cobb et al, 2010;Maiti et al, 2010). Gene polymorphisms in IL-10, IL-6, IL-1 receptor antagonist, IL-4 receptor , TNF-, IFN- and TGF-1 have also been associated with pSS (Cobb et al, 2008).…”

Section: Genetic Factors 331 Genetic Variationmentioning

confidence: 99%

Primary Sjögren’s Syndrome: Current Pathophysiological, Diagnostic and Therapeutic Advances

Delporte¹,

Perret²,

Soyfoo³

2011

Autoimmune Disorders - Current Concepts and Advances From Bedside to Mechanistic Insights

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Genetic association between methyl-CpG binding protein 2 (MECP2) and primary Sjogren's syndrome

Cited by 32 publications

References 10 publications

MeCP2 enforces Foxp3 expression to promote regulatory T cells’ resilience to inflammation

MeCP2 enforces Foxp3 expression to promote regulatory T cells’ resilience to inflammation

Alterations in type I hemidesmosome components suggestive of epigenetic control in the salivary glands of patients with Sjögren's syndrome

Primary Sjögren’s Syndrome: Current Pathophysiological, Diagnostic and Therapeutic Advances

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