title: An epigenetic silencing pathway controlling T helper 2 cell lineage commitment.
abstract: 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.
authors: Institut Curie Research Center, 26 rue d’Ulm, 75248 Paris Cedex 05, France.
authors: Rhys S
authors: RS
authors: Allan
authors: Elina
authors: E
authors: Zueva
authors: Florence
authors: F
authors: Cammas
authors: Heidi A
authors: HA
authors: Schreiber
authors: Vanessa
authors: V
authors: Masson
authors: Gabrielle T
authors: GT
authors: Belz
authors: Danièle
authors: D
authors: Roche
authors: Christèle
authors: C
authors: Maison
authors: Jean-Pierre
authors: JP
authors: Quivy
authors: Geneviève
authors: G
authors: Almouzni
authors: Sebastian
authors: S
authors: Amigorena
mesh_terms: D000818:Animals; D001249:Asthma / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D008297:Male; D008780:Methyltransferases / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000172:deficiency / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology* / Q000201:enzymology / Q000276:immunology*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D012097:Repressor Proteins; D000090266:Chromobox Protein Homolog 5; C498700:Suv39h1 protein, mouse; D008780:Methyltransferases