title: Histone modifications of Notch1 promoter affect lung CD4+ T cell differentiation in asthmatic rats.
abstract: Asthma is an inflammatory disease of the airways, and the current treatment in managing asthma is the control of inflammation. Notch signaling pathway has been linked to T-cell imbalance. The present study aimed to explore the histone modifications of Notch1 promoter in normal and asthmatic lung CD4+ T cells. Chromatin immunoprecipitation analysis showed that the acetylation levels of total H3, H4, site-specific H3K9, H3K14, H3K27, H3K18, H4K16, and the trimethylation levels of H3K4, H3K79 of Notch1 gene promoter were increased significantly in asthmatic lung CD4+ T cells compared to the control group, which correlated with increased P300, PCAF activity and decreased HDAC1, HDAC2 activity. After intervention of garcinol, a potent inhibitor of histone acetyltransferases, in asthmatic lung CD4+ T cells, HAT activity decreased significantly and the increased Notch1 and hes-1 expression was reversed. The total H3ac, H4ac, site-specific H3K9ac, H3K14ac, H3K27ac, H3K18ac, H4K16ac and H3K79me3 levels of Notch1 gene promoter decreased significantly, and the H3K4me3, H3K9me3, H4K20me3 levels had no significant difference. We further investigated the suppressive effects of GAR on asthmatic parameters. Results showed that the levels of IL-4, IL-5 and IL-13 were significantly reduced and a small reverse trend was found in the level of IFN-g after GAR treatment. Furthermore, the expression of NF-&#954;B and AP-1 reduced significantly. These results suggest that asthma is associated with changes in the epigenetic status of Notch1 promoter, including abnormal histone acetylation and methylation, and GAR may have applications in the treatment of asthma.
authors.affiliation: Department of Respiratory Medicine, XinHua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Z-L
authors.initials: ZL
authors.lastname: Cui
authors.forename: W
authors.initials: W
authors.lastname: Gu
authors.forename: T
authors.initials: T
authors.lastname: Ding
authors.forename: X-H
authors.initials: XH
authors.lastname: Peng
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: C-Y
authors.initials: CY
authors.lastname: Luan
authors.forename: R-C
authors.initials: RC
authors.lastname: Han
authors.forename: W-G
authors.initials: WG
authors.lastname: Xu
authors.forename: X-J
authors.initials: XJ
authors.lastname: Guo
mesh_terms: D000107:Acetylation; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D001249:Asthma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D056284:Histone Deacetylase 1 / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008745:Methylation; D016328:NF-kappa B / Q000378:metabolism; D010047:Ovalbumin; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D051881:Receptor, Notch1 / Q000235:genetics*; D015398:Signal Transduction; D013729:Terpenes / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D000072056:Transcription Factor HES-1; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D018927:Anti-Asthmatic Agents; D051792:Basic Helix-Loop-Helix Proteins; D016207:Cytokines; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D018398:Homeodomain Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; D010047:Ovalbumin; D051881:Receptor, Notch1; D013729:Terpenes; D018808:Transcription Factor AP-1; D000072056:Transcription Factor HES-1; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C489735:Hes1 protein, rat; C497763:Notch1 protein, rat; C515890:Hdac1 protein, rat; C533426:Hdac2 protein, rat; C054597:garcinol