β-Arrestin-1 Regulates Epigenetics of Whole Genome in Chronic Myeloid Leukemia Cells

Abstract 4636

Chronic myeloid leukemia (CML) is a clonal myeloproliferative expansion of transformed, primitive hematopoietic progenitor cells, which is an incidence of 1 to 2 cases per 100,000 people per year and accounts for 15 percent of adult leukemias. Although the-philadelphia (Ph) chromosome and the BCR-ABL fusion gene are known as the featured molecular characteristic, the pathogenetic mechanism of CML is still not fully clear. In recent years, epigenetics, the heritable changes of gene expression without change in DNA sequence, has rapid development in the area of regulating gene transcription and expression. The epigenetic modification includes the types of DNA methylation, histone acetylation, protein phosphorylation, ubiquitination, chromatin remodeling, and so on. β-arrestin1, one key member of arrestin family that are multifunctional scaffold proteins, was reported to regulate histone acetylation and gene transcription in GPCR signaling. However, little is known about the role of β-arrestin1 in mediating the whole genome epigenetics, especially in CML. Here, we firstly knocked down β-arrestin1 expression in K562 cells, the typical cell lines for CML, and then measured and analyzed the alterations of whole genome epigenetics by combinedly using chromatin immunoprecipitation(ChIP)-on-chip and methylation chip. The data from ChIP-on-chip showed that β-arrestin-1 mediated 7498 genes histone H4 acetylation, mainly afffected the genes of cell part, cell vability and prolieration when β-arrestin1 was knocked down in CML cells. Clustering analysis showed that these affected genes of histone H4 acetylation were involved in MAPK signaling. Moreover, the data from methylation chip indicated that the methylative level of the whole genome were decreased, and genome hypermethylated was more obvious than hypomethylated, when β-arrestin1 knockout. Further analysis found that the differences of CpG island number primarily located in 500–1000bp promoter region. And methylative modifications of influenced CpG island number easily occurred in chromosome 1, 4, 13, 14, 19 and X, compared with other chromosomes. Most interestingly, the distinct changes of acetylation and methylation for some cell part genes (ZNF259, IL23A, COPS6 and COASY) were simultaneously regulated by β-arrestin1 with GO analysis, which could shift the epigenetic alterations by β-arrestin1 in CML cells. These common genes both involved in these two kinds of epigenetics, and function analysis are further study. Taken together, our study shed new light on β-arrestin1 in regulating epigenetics of whole genome in chronic myeloid leukemia cells.