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

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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.