ROLE OF eARIDs IN LYMPHOCYTE FUNCTION AND DEVELOPMENT

ARID （AT- Rich Interaction Domain）转录因子与染色质重塑和生长失调有关。在ARID家族的13个成员中，有两个被称为earid，因为它们在ARID DNA结合域之外显示了扩展的(e)身份：Bright （B细胞特异性的IgH转录调节剂）和Bdp （Bright- drilike protein）。Bright作为核矩阵相关区域（MARs）内特定基序（P位点）的正转录激活剂，位于IgH内含子增强子（Em）和VH $107家族V1成员的5′侧。在人(h)和小鼠(m) B细胞分化中，Bright仅限于早期的preB和生发中心B细胞。对这两个物种的Bdp知之甚少。目的1提出了与Bright相关的Bdp表达、功能和定位的完整表征。在目标2中我们

ARID (AT- Rich Interaction Domain) transcription factors have been implicated in chromatin remodeling and growth deregulation. Of the 13 members of the ARID family, two are termed eARIDs because they show extended (e) identity beyond the ARID DNA binding domain: Bright (for B cell specific regulator of IgH transcription) and Bdp (for Bright-Dri-like protein). Bright functions as a positive transcriptional activator of specific motifs (P sites) within nuclear matrix associated regions (MARs) flanking the IgH intronic enhancer (Em) and 5' to the V1 member of the VH $107 family. In human (h) and mouse (m) B cell differentiation, Bright is restricted to early preB and germinal center B cells. Little is known about Bdp in either species. Aim 1 proposes a full characterization of Bdp expression, function, and localization relative to Bright. In Aim 2 we propose to identify and validate genes in additional to IgH that are activated by the eARIDs. Our initial focus will include 5 targets that define a potential role for Bright in cell survival. There have been no ARID knockouts reported. Conventional targeted disruption of the Bright gene in mice leads to embryonic lethality (Progress Report). In Aim 3, we propose a conditional knockout approach for eliminating Bright only in B cells. We will evaluate Bright null mice in the context of normal and malignant B cell biology and with regard to the developmental and repertoire dysfunction proposed for Bright in X-linked immunodeficiency disease. We propose to create Bdp null mice using one of the above strategies.