Regulation of gene expression by HDAC3

摘要 将多能祖细胞分化为T细胞需要转录和转录之间复杂的相互作用 作为胸腺细胞的调节器经历了发育的每一个阶段。基因的表达是通过 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 可获得性和转录。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具有特定的或重叠的功能还没有被很好地理解。我们的工作证明了 HDAC3在T细胞发育中具有独特的作用，这是任何其他共表达的基因所不能弥补的 HDAC家庭成员。HDAC3是DP存活和阳性选择所必需的。CD2-ICRE HDAC3 CKO小鼠 在胸腺细胞阳性选择严重受阻的情况下，DP胸腺细胞的数量减少，导致很少 产生SP胸腺细胞。从机制上讲，CD2-ICRE HDAC3 CKO小鼠的正选择受阻是由于 由于未能下调单个基因，RoRγt。类似地，需要HDAC3来抑制 DP胸腺细胞中的嘌呤能受体P2RX7和表达增加的P2RX7与DP的缺陷有关 CD2-ICRE HDAC3 CKO小鼠存活。需要HDAC3来抑制基因的过早表达 对CD8血统的承诺。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，是限制性的，而不是全局的。正常表达的基因 限制为其他(非T)造血系在没有HDAC3的情况下保持关闭，并进行家务管理 在WT和HDAC3缺乏的DP胸腺细胞中，基因的表达水平相似。因此，HDAC3 不是基因调控的通用或一般修饰物。相反，HDAC3在一小部分 对DP生存、阳性选择和CD4/CD8谱系选择至关重要的基因。这件事的重点是 建议是定义HDAC3是如何招募到DP胸腺细胞中的这些基因的，染色质的变化 它们伴随着HDAC3的招募和对HDAC3功能至关重要的结合伙伴。

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.