COBRE: NDSU: PROJECT 1: EPIGENETIC REGULATION OF VASOACTIVE INTESTINAL PEPTIDE

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 近一半的白血病患者将在Ikaros(IK)基因的DNA结合域发生缺失。该项目的长期目标是了解IK如何在细胞转化以及正常的造血和胎儿发育过程中双向和表观遗传地调节转录表达。IK是一种肿瘤抑制因子，是一种表观遗传转录因子，主要集中在转录抑制核区，称为着丝粒周围异染色质(PC-HC)，并与多种复合体共定位，包括转录抑制核小体重塑复合体(NuRD)。 中心假设是，IK通过与VPACR-1启动子中的IK基序物理结合而沉默VPACR-1的表达，从而导致关键的Sp1共激活因子的置换。此外，IK将抑制性HDAC/NuRD复合体招募到VPACR-1启动子上，产生低乙酰化组蛋白，进一步抑制激活的CD4T细胞中VPACR-1的调节。 该项目的意义在于通过更深入地了解IK调节VPACR-1的调节机制，从而更好地了解白细胞的增殖和分化计划。VPACR-1是一种在免疫隔间高表达的GPCR基因，调节细胞的增殖和分化。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Nearly half of leukemic patients will have deletions in the DNA-binding domain of the Ikaros (IK) gene. The long-term goal of this project is to understand how IK bidirectionally and epigenetically modulates transcriptional expression during cellular transformation as well as during normal hematopoiesis and fetal development. IK, a tumor-suppressor, epigenetic transcription factor, preferentially concentrates in transcriptionally repressive nuclear domains called pericentrimeric heterochromatin (PC-HC) and is co-localized with several complexes, including the transcriptionally repressive nucleosome remodeling complex (NuRD). The central hypothesis is that IK silences vasoactive intestinal peptide receptor-1(VPACR-1) expression by physically binding to IK motifs found in the VPACR-1 promoter that results in the displacement of a crucial Sp1 co-activator. Additionally, IK recruits the repressive HDAC/NuRD complex to the VPACR-1 promoter generating a hypo-acetylated histone profile that further suppresses VPACR-1 regulation in activated CD4 T cells. The significance of this project is to understand leukocyte proliferation and differentiation programs better by gaining a greater insight into the regulatory mechanisms by which IK regulates VPACR-1, a highly expressed GPCR gene expressed in the immune compartment that modulates cellular proliferation and differentiation.