» Articles » PMID: 24958888

MeCP2 Enforces Foxp3 Expression to Promote Regulatory T Cells' Resilience to Inflammation

Overview
Specialty Science
Date 2014 Jun 25
PMID 24958888
Citations 36
Authors
Affiliations
Soon will be listed here.
Abstract

Forkhead box P3(+) (Foxp3(+)) regulatory T cells (Tregs) are crucial for peripheral tolerance. During inflammation, steady Foxp3 expression in Tregs is essential for maintaining their lineage identity and suppressive function. However, the molecular machinery governing Tregs' resilience to inflammation-induced Foxp3 destabilization remains elusive. Here, we demonstrate that methyl-CpG binding protein 2 (MeCP2), an eminent epigenetic regulator known primarily as the etiological factor of Rett syndrome, is critical to sustain Foxp3 expression in Tregs during inflammation. In response to inflammatory stimuli, MeCP2 is specifically recruited to the Conserved Non-Coding sequence 2 region of the foxp3 locus, where it collaborates with cAMP responsive element binding protein 1 to promote local histone H3 acetylation, thereby counteracting inflammation-induced epigenetic silencing of foxp3. Consequently, Treg-specific deletion of MeCP2 causes spontaneous immune activation in mice and failure in protection against autoimmunity. Furthermore, we demonstrate that Foxp3 expression in MeCP2-deficient Tregs diminishes with time, resulting in their failure to suppress effector T-cell-mediated colitis. Thus, MeCP2 serves as a critical safeguard that confers Tregs with resilience against inflammation.

Citing Articles

Versatile functions of methyl-CpG-binding domain 2 (MBD2) in cellular characteristics and differentiation.

Lekesiz R, Koca K, Kugu G, Caliskaner Z Mol Biol Rep. 2025; 52(1):316.

PMID: 40089655 DOI: 10.1007/s11033-025-10411-8.


Molecular Mechanisms of Rett Syndrome: Emphasizing the Roles of Monoamine, Immunity, and Mitochondrial Dysfunction.

Goncalez J, Shen J, Li W Cells. 2025; 13(24.

PMID: 39768168 PMC: 11674639. DOI: 10.3390/cells13242077.


Comprehensive analysis reveals the prognostic and immunogenic characteristics of DNA methylation regulators in lung adenocarcinoma.

Huang J, Huang C, Huang C, Xiang Z, Ni Y, Zeng J Respir Res. 2024; 25(1):74.

PMID: 38317133 PMC: 10845581. DOI: 10.1186/s12931-024-02695-4.


DNA demethylation in the hypothalamus promotes transcription of Agtr1a and Slc12a2 and hypertension development.

Ghosh K, Zhou J, Shao J, Chen S, Pan H J Biol Chem. 2023; 300(2):105597.

PMID: 38160798 PMC: 10830874. DOI: 10.1016/j.jbc.2023.105597.


Methyl-CpG-Binding Protein 2 Emerges as a Central Player in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders.

Mehmood A, Shah S, Guo R, Haider A, Shi M, Ali H Cell Mol Neurobiol. 2023; 43(8):4071-4101.

PMID: 37955798 PMC: 11407427. DOI: 10.1007/s10571-023-01432-7.


References
1.
Sawalha A, Webb R, Han S, Kelly J, Kaufman K, Kimberly R . Common variants within MECP2 confer risk of systemic lupus erythematosus. PLoS One. 2008; 3(3):e1727. PMC: 2253825. DOI: 10.1371/journal.pone.0001727. View

2.
Josefowicz S, Lu L, Rudensky A . Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol. 2012; 30:531-64. PMC: 6066374. DOI: 10.1146/annurev.immunol.25.022106.141623. View

3.
Quaderi N, Meehan R, Tate P, Cross S, Bird A, Chatterjee A . Genetic and physical mapping of a gene encoding a methyl CpG binding protein, Mecp2, to the mouse X chromosome. Genomics. 1994; 22(3):648-51. DOI: 10.1006/geno.1994.1442. View

4.
Chrivia J, Kwok R, Lamb N, Hagiwara M, Montminy M, Goodman R . Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature. 1993; 365(6449):855-9. DOI: 10.1038/365855a0. View

5.
Sakaguchi S, Yamaguchi T, Nomura T, Ono M . Regulatory T cells and immune tolerance. Cell. 2008; 133(5):775-87. DOI: 10.1016/j.cell.2008.05.009. View