FoxP3 interacts with linker histone H1.5 to modulate gene expression and program Treg cell activity
| Autor: | Jianmei Gao, Derek A. Holmes, Jun-ichi Nunoya, Derya Unutmaz, Lishan Su, Rui Wang, Stephanie L. Mackey-Cushman |
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| Rok vydání: | 2011 |
| Předmět: |
Regulatory T cell
Immunology chemical and pharmacologic phenomena T-Lymphocytes Regulatory Jurkat cells Article Histones Jurkat Cells 03 medical and health sciences 0302 clinical medicine Histone H1 Genetics medicine Humans Gene silencing CTLA-4 Antigen Amino Acid Sequence IL-2 receptor Promoter Regions Genetic Cells Cultured Genetics (clinical) 030304 developmental biology Regulation of gene expression 0303 health sciences biology HEK 293 cells Forkhead Transcription Factors hemic and immune systems Molecular biology HEK293 Cells Histone medicine.anatomical_structure Gene Expression Regulation 030220 oncology & carcinogenesis Mutation biology.protein Interleukin-2 Protein Binding |
| Zdroj: | Genes and immunity |
| ISSN: | 1476-5470 1466-4879 |
| DOI: | 10.1038/gene.2011.31 |
| Popis: | The forkhead box transcription factor FoxP3 controls the development and function of CD4+CD25+ regulatory T (Treg) cell. FoxP3 modulates gene expression in Treg cells by multiple epigenetic mechanisms that are not clearly defined. We identified FoxP3-interacting proteins in human T cells by co-immunoprecipitation/MS. We discovered that FoxP3 interacted with linker histone H1.5 via the leucine zipper (LZ) domain. Two independent IPEX patient-derived single residue mutations in the LZ of FoxP3 both abrogated its interaction with H1.5. Functionally, FoxP3 and H1.5 cooperatively repressed interleukin-2 (IL-2) expression in human T cells; and silencing of H1.5 expression inhibited the ability of FoxP3 to suppress IL-2 expression. We show that FoxP3 specifically enhanced H1.5 association at the IL-2 promoter, but reduce its association at the CTLA4 promoter, correlated with higher or lower histone acetylation of the respective promoters. Finally, silencing of H1.5 expression in human Treg cells impaired the Treg function to suppress target T cells. We conclude that FoxP3 interacts with H1.5 to alter its binding to target genes to modulate their expression and to program Treg function. |
| Databáze: | OpenAIRE |
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