A Function Of β-Arrestin 1 In Nucleus: Epigeneticly Regulates Gene Transcription And Its Role In Autoimmunity

Chromatin modification is considered to be a fundamental mechanism of regulating gene expression to generate coordinated responses to environmental changes.β-arrestin 1 (βarr1) is a multifunctional molecule active in many signaling pathways. In the first part of this thesis, we show that nuclearβarr1 accumulation caused by certain GPCR stimulation orβarr1 overexpression, induces its binding at specific gene promoters where it facilitates the recruitment of histone acetyltransferase p300,resulting in enhanced local histone H4 acetylation and transcription of these genes. These results reveal a novel function ofβarr1 on epigenetic regulation, and elucidate a direct way for GPCR signaling from cell membrane to the nucleus. Further, in the second part of this thesis, we foud a function ofβarr1 in CD4~+ T cells. As demostrated by in vitro and in vivo experiments, nuclearβarr1 epigeneticly regulates Bcl-2 expression and the survival of CD4~+ T cells. Importantly,βarr1 knock out mice were found to be significantly more resistant to experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS), whileβarr1 over-expression in transgenic mice increased susceptibility to the disease. Moreover, we found that the expression ofβarr1 is significantly increased in CD4~+ T cells isolated from multiple sclerosis patients and EAE mice, and thisβarr1 upregulation renders the auto-reactive CD4~+ T cells more resistant to cytokine-withdrawal-induced apoptosis. Thus, these results not only reveal an improtant biological significance of the nuclear function ofβarr1, epigeneticly regulating gene expression, and also demostrate a novel regulatory mechanism critical for CD4~+ T cell survival and autoimmunity, and suggest a potential new therapeutic strategy for autoimmune disease.