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

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 近一半的白血病患者将在Ikaros（IK）基因的DNA结合结构域中缺失。这个项目的长期目标是了解IK如何双向和表观遗传调节细胞转化过程中的转录表达，以及在正常的造血和胎儿发育。IK是一种肿瘤抑制、表观遗传转录因子，优先集中在称为中心异染色质（pericentrimeric heterochromatin，PC-HC）的转录抑制性核结构域，并与包括转录抑制性核小体重塑复合物（transcriptionally repressive nucleosome remodeling complex，NuRD）在内的几种复合物共定位。 中心假设是IK沉默血管活性肠肽受体-1（VPACR-1）的表达，通过物理结合到VPACR-1启动子中发现的IK基序，导致关键的Sp1辅激活剂的置换。此外，IK将抑制性HDAC/NuRD复合物募集到VPACR-1启动子，产生低乙酰化组蛋白谱，其进一步抑制活化的CD 4 T细胞中的VPACR-1调节。 该项目的意义在于通过更深入地了解IK调节VPACR-1的调节机制来更好地理解白细胞增殖和分化程序，VPACR-1是一种在免疫室中表达的高表达GPCR基因，其调节细胞增殖和分化。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.