Regulation of gene expression by HDAC3

HDAC3 对基因表达的调节

• 批准号: 10667604
• 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/10667604
• 关键词: ATAC-seq; Acetylation; 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; Modification; Multienzyme Complexes; Multipotent Stem Cells; Mus; NCOR1 gene; NCOR2 gene; Neighborhoods; Nucleosomes; Pattern; Positioning Attribute; 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; 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.

抽象的 多能祖细胞分化为 T 细胞需要转录因子之间复杂的相互作用 胸腺细胞在各个发育阶段都发挥着调节作用。基因表达通过以下方式控制 调节转录激活和染色质可及性。组蛋白脱乙酰酶 (HDAC) 限制染色质 可访问性和转录。 DP 胸腺细胞共表达所有 18 个 HDAC 家族成员，但是否共表达 表达的 HDAC 具有特定或重叠的功能尚不清楚。我们的工作已经证明 HDAC3 在 T 细胞发育中具有独特的作用，这是任何其他共表达都无法弥补的 HDAC家族成员。 HDAC3 是 DP 存活和正选择所必需的。 CD2-icre HDAC3 cKO 小鼠 DP 胸腺细胞数量减少，胸腺细胞阳性选择严重受阻，导致很少 SP胸腺细胞产生。从机制上讲，CD2-icre HDAC3 cKO 小鼠中阳性选择的阻断是由于 未能下调单个基因 RORγt。类似地，HDAC3 需要抑制 DP 胸腺细胞中的嘌呤能受体 P2RX7，P2RX7 表达增加导致 DP 缺陷 CD2-icre HDAC3 cKO 小鼠的存活率。 HDAC3 需要抑制指导基因的过早表达 对 CD8 谱系的承诺。基因表达和 H3K27 或 H3K9 组蛋白乙酰化的变化 在 HDAC3 缺陷的 DP 胸腺细胞中，这种影响是有限的，而不是整体的。表达正常的基因 在缺乏 HDAC3 的情况下，仅限于其他（非 T）造血谱系的功能仍然关闭，并且内务处理 WT 和 HDAC3 缺陷的 DP 胸腺细胞之间的基因表达水平相似。因此，HDAC3 不是基因调控的通用或一般修饰剂。相反，HDAC3 在一小部分具有特定功能 对于 DP 生存、正选择和 CD4/CD8 谱系选择至关重要的基因。本次的重点 提议是定义 HDAC3 如何被招募到 DP 胸腺细胞中的那些基因，即染色质的改变 它伴随着 HDAC3 招募和对 HDAC3 功能至关重要的结合伙伴。