Regulation of gene expression by HDAC3

HDAC3 对基因表达的调节

• 批准号: 10225415
• 负责人: Virginia Smith Shapiro
• 金额: $ 50.57万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225415
• 关键词: ATAC-seq; Binding; CD8B1 gene; Chromatin; Chromatin Loop; Complex; DNA; Defect; Development; Enhancers; Event; Failure; Family; Family member; Gene Expression; Gene Expression Regulation; General Qualifier; Genes; Genetic Transcription; Genomics; HDAC3 gene; Hematopoietic; Histone Acetylation; Histone Deacetylase; Histone Deacetylation; Histone H3; Histones; Holoenzymes; Housekeeping Gene; Lysine; Maintenance; Mediating; Mediator of activation protein; Modification; Multienzyme Complexes; Multipotent Stem Cells; Mus; NCOR1 gene; NCOR2 gene; Neighborhoods; Nucleosomes; Pattern; Process; Proteins; Purinoceptor; RNA Binding; RNA Polymerase II; Regulation; Role; Site; T-Cell Development; T-Lymphocyte; Thymocyte Development; Tissues; Transcription Initiation; Transcription Initiation Site; Transcriptional Activation; Tumor stage; Untranslated RNA; Up-Regulation; Work; Writing; base; chromatin remodeling; gene repression; histone acetyltransferase; member; non-histone protein; premature; promoter; recruit; thymocyte; transcription factor

Abstract Differentiation of multi-potent progenitors into T cells requires an intricate interplay between transcriptional regulators as thymocytes proceed through each stage of development. Gene expression is controlled through regulating transcriptional activation and chromatin accessibility. Histone deacetylases (HDACs) limit chromatin accessibility and transcription. DP thymocytes co-express all 18 HDAC family members, but whether co- expressed HDACs have specific or overlapping functions is not well understood. Our work has demonstrated that HDAC3 has a unique role in T cell development, which is not compensated for by any other co-expressed HDAC family member. HDAC3 is required for DP survival and positive selection. CD2-icre HDAC3 cKO mice have decreased numbers of DP thymocytes with a severe block in thymocyte positive selection resulting in few SP thymocytes produced. Mechanistically, the block in positive selection in CD2-icre HDAC3 cKO mice is due to a failure to downregulate a single gene, RORγt. Similarly, HDAC3 is required to suppress expression of the purinergic receptor P2RX7 in DP thymocytes, and increased P2RX7 expression contributes to the defect in DP survival in CD2-icre HDAC3 cKO mice. HDAC3 is required to inhibit premature expression of genes that direct commitment to the CD8 lineage. Changes in gene expression and H3K27 or H3K9 histone acetylation were restricted, rather than global, in HDAC3-deficient DP thymocytes. Genes whose expression is normally restricted to other (non-T) hematopoietic lineages remain off in the absence of HDAC3, and housekeeping genes are expressed at similar levels between WT and HDAC3-deficient DP thymocytes. Therefore, HDAC3 is not a generic or general modifier of gene regulation. Instead, HDAC3 has specific functions in a small set of genes that are critical for DP survival, positive selection and CD4/CD8 lineage choice. The focus of this proposal is to define how HDAC3 is recruited to those genes in DP thymocytes, the alterations in chromatin which accompany HDAC3 recruitment and the binding partners critical for HDAC3 function.

摘要