Structure/Function of CBFbeta

描述（由申请人提供）：核心结合因子（CBF）是一个转录因子小家族，由Runx1、Runx2或Runx3基因编码的DNA结合亚基和Cbfb基因编码的常见非DNA结合CBF 2亚基组成。我们发现，CBF2水平降低（正常水平的15%）的小鼠产生除T细胞和NK细胞外的所有血细胞谱系。CBF2不足小鼠的T细胞发育在特化阶段中止，因为T细胞分化的最早标志物不能表达。NK细胞发育也在NK祖细胞和未成熟NK细胞之间的过渡早期失败。我们建议通过确定NK祖细胞向未成熟NK细胞进展所需的DNA结合Runx亚基（或亚基）来进一步表征CBF2不足引起的NK细胞缺陷。我们还将使用T和NK细胞发育的体外测定来探测CBF在这些谱系中的生化功能。具体来说，我们将确定和表征由CBF招募到T和NK细胞中的靶基因的染色质重塑蛋白，并评估这些蛋白与T和NK细胞发育的相关性。我们将评估CBF相互作用蛋白质的染色质占有率，以确定它们是否与CBF结合的所有基因或基因子集相关，以及它们的占有率是否与活性或非活性染色质状态相关。 这些研究旨在了解淋巴细胞形成所必需的蛋白质如何发挥其功能。这是一个重要的研究领域，因为淋巴细胞发育的破坏可能导致免疫紊乱、白血病和淋巴瘤。

DESCRIPTION (provided by applicant): The core binding factors (CBFs) are a small family of transcription factors that consist of a DNA binding subunit encoded by the Runx1, Runx2, or Runx3 genes, and a common non-DNA binding CBF2 subunit encoded by the Cbfb gene. We showed that mice with reduced (15% of normal) CBF2 levels generate all blood cell lineages with the exception of T and NK cells. T cell development in CBF2-insufficient mice aborts at the specification stage, as the very earliest markers of T cell differentiation fail to be expressed. NK cell development also fails very early, at the transition between NK progenitors and immature NK cells. We propose to further characterize the NK cell defect caused by CBF2 insufficiency by determining which DNA-binding Runx subunit (or subunits) are required for the progression of NK progenitors to immature NK cells. We will also use in vitro assays of T and NK cell development to probe the CBF's biochemical functions in these lineages. Specifically, we will identify and characterize chromatin-remodeling proteins recruited by the CBFs to their target genes in T and NK cells, and assess the relevance of these proteins for T and NK cell development. We will assess chromatin occupancy by the CBF-interacting proteins to determine whether they associate with all or a subset of genes bound by the CBFs, and if their occupancy correlates with active or inactive chromatin states. Project Narrative: These studies aim to understand how proteins that are essential for lymphocyte formation perform their functions. This is an important area of research because disruption of lymphocyte development can lead to immune disorders, leukemia, and lymphoma.