Document Detail

An epigenetic silencing pathway controlling T helper 2 cell lineage commitment.
MedLine Citation:
PMID:  22763435     Owner:  NLM     Status:  MEDLINE    
During immune responses, naive CD4+ T cells differentiate into several T helper (TH) cell subsets under the control of lineage-specifying genes. These subsets (TH1, TH2 and TH17 cells and regulatory T cells) secrete distinct cytokines and are involved in protection against different types of infection. Epigenetic mechanisms are involved in the regulation of these developmental programs, and correlations have been drawn between the levels of particular epigenetic marks and the activity or silencing of specifying genes during differentiation. Nevertheless, the functional relevance of the epigenetic pathways involved in TH cell subset differentiation and commitment is still unclear. Here we explore the role of the SUV39H1–H3K9me3–HP1α silencing pathway in the control of TH2 lineage stability. This pathway involves the histone methylase SUV39H1, which participates in the trimethylation of histone H3 on lysine 9 (H3K9me3), a modification that provides binding sites for heterochromatin protein 1α (HP1α) and promotes transcriptional silencing. This pathway was initially associated with heterochromatin formation and maintenance but can also contribute to the regulation of euchromatic genes. We now propose that the SUV39H1–H3K9me3–HP1α pathway participates in maintaining the silencing of TH1 loci, ensuring TH2 lineage stability. In TH2 cells that are deficient in SUV39H1, the ratio between trimethylated and acetylated H3K9 is impaired, and the binding of HP1α at the promoters of silenced TH1 genes is reduced. Despite showing normal differentiation, both SUV39H1-deficient TH2 cells and HP1α-deficient TH2 cells, in contrast to wild-type cells, expressed TH1 genes when recultured under conditions that drive differentiation into TH1 cells. In a mouse model of TH2-driven allergic asthma, the chemical inhibition or loss of SUV39H1 skewed T-cell responses towards TH1 responses and decreased the lung pathology. These results establish a link between the SUV39H1–H3K9me3–HP1α pathway and the stability of TH2 cells, and they identify potential targets for therapeutic intervention in TH2-cell-mediated inflammatory diseases.
Rhys S Allan; Elina Zueva; Florence Cammas; Heidi A Schreiber; Vanessa Masson; Gabrielle T Belz; Danièle Roche; Christèle Maison; Jean-Pierre Quivy; Geneviève Almouzni; Sebastian Amigorena
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Nature     Volume:  487     ISSN:  1476-4687     ISO Abbreviation:  Nature     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-12     Completed Date:  2012-08-09     Revised Date:  2012-09-24    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  England    
Other Details:
Languages:  eng     Pagination:  249-53     Citation Subset:  IM    
Institut Curie Research Center, 26 rue d’Ulm, 75248 Paris Cedex 05, France.
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MeSH Terms
Asthma / enzymology,  immunology,  pathology
Cell Differentiation / genetics,  immunology
Cell Lineage / genetics,  immunology
Chromosomal Proteins, Non-Histone / metabolism
Disease Models, Animal
Epigenesis, Genetic*
Gene Expression Regulation
Gene Silencing
Histones / metabolism
Methyltransferases / deficiency,  metabolism
Mice, Inbred C57BL
Promoter Regions, Genetic
Repressor Proteins / deficiency,  metabolism
Th1 Cells / metabolism
Th2 Cells / cytology*,  enzymology,  immunology*
Reg. No./Substance:
0/Chromosomal Proteins, Non-Histone; 0/Histones; 0/Repressor Proteins; 107283-02-3/heterochromatin-specific nonhistone chromosomal protein HP-1; EC 2.1.1./Suv39h1 protein, mouse; EC 2.1.1.-/Methyltransferases
Comment In:
Nat Rev Immunol. 2012 Aug;12(8):549   [PMID:  22828901 ]

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