Histone H3K9 methyltransferase (HMTase) G9a-mediated transcriptional repression is a major epigenetic silencing mechanism. UHRF1 (ubiquitin-like with PHD and ring finger domains 1) binds to hemimethylated DNA and plays an essential role in the maintenance of DNA methylation. Here, we provide evidence that UHRF1 is transcriptionally downregulated by H3K9 HMTase G9a. We found that increased expression of G9a along with transcription factor YY1 specifically represses UHRF1 transcription during TPA-mediated leukemia cell differentiation. Using ChIP analysis, we found that UHRF1 was among the transcriptionally silenced genes during leukemia cell differentiation. Using a DNA methylation profiling array, we discovered that the UHRF1 promoter was hypomethylated in samples from leukemia patients, further supporting its overexpression and oncogenic activity. Finally, we showed that G9a regulates UHRF1-mediated H3K23 ubiquitination and proper DNA replication maintenance. Therefore, we propose that H3K9 HMTase G9a is a specific epigenetic regulator of UHRF1.
Abstract. The nuclear phosphoprotein deK is abundantly present in cells and is implicated in diseases including leukemia and autoimmune disorders. deK has three highly acidic amino acid domains and inhibits histone acetyltransferase activity by binding directly to histones. in a previous study, differentially regulated proteins under deK knockdown conditions, including the up-regulated protein 1-cys peroxiredoxin (1-cys Prx), were identified by proteome analysis. Here, an in vivo reporter assay with short hairpin rna-mediated deK knockdown revealed that deK negatively regulated 1-cys Prx transcription, and that the nF-κB subunit p65 had a synergistic effect on this deK-mediated repression. Both proteins are recruited to the 1-cys Prx promoter region and regulate its transcription. our study demonstrates that deK modulates the transcriptional regulation of the target gene through protein interaction with other regulatory proteins. IntroductionThe DEK protein was first identified in a specific chromosomal translocation t(6;9)(p23;q34) in an acute myelogenous leukemia, which results in the formation of a fusion gene with the can nucleoporin protein nuP214 (1). This translocated fusion gene makes a fusion protein, in which part of the n-terminal (1-349 amino acids) of deK is fused with part of the c-terminal (813-2,090 amino acids) of can. The deK protein, as a phosphoprotein, is an abundantly and ubiquitously expressed nuclear protein with two functional domains (SaP and dna binding/multimerization), several phosphorylation sites and three highly acidic domains (2,3). deK binds dna and induces deK-deK multimerization in a phosphorylation-dependent manner (4). a recent report showed that a highly acidic domain in deK inhibits histone acetyltransferase (HAT) activity through histone binding (2). It has been revealed that DEK influences chromatin remodeling through the alteration of chromatin topology (5,6). deK also regulates transcriptional activity by recruiting transcriptional co-repressors, such as hdaxx and histone deacetylase-2, to chromatin (7).deK is also involved in carcinogenesis and autoimmune diseases, such as systemic lupus erythematosus, juvenile rheumatoid arthritis and ataxia telangiectasia (8). a recent proteomic analysis revealed that deK knockdown up-regulated 1-cys peroxiredoxin (1-cys Prx) (Prx 6) and caused the hyperacetylation of histones around the 1-cys Prx promoter (9).1-cys Prx is one of six Prx isoforms, and is expressed in various tissues -in particular liver tisses -related to the protection of cellular oxidative stresses (10).nF-κB is a transcription factor with multiple biological functions, including immune and inflammatory response, cell growth and differentiation, and the suppression of apoptosis (11). The nF-κB family consists of five members, p65/RelA, p50 (p105), p52 (p100), relB and c-rel (12). a previous study showed that the p65 subunit of nF-κB interacts with deK (13).In this study, we identified the negative regulatory role of deK in 1-cys Prx transcription: its knockdown re...
Even though exposure to benzene has been linked to a variety of cancers including leukemia, the detailed molecular mechanisms relevant to benzene-induced carcinogenesis remain to be clearly elucidated. In this study, we evaluated the effects of benzene on differential gene expression in a leukemia cell line. The K562 leukemia cell line used in this study was cultured for 3 h with 10 mM benzene and RNA was extracted. To analyze the gene expression profiles, a 41,000 human whole genome chip was employed for cDNA microarray analysis. We initially identified 6,562 genes whose expression was altered by benzene treatment. Among these, 3,395 genes were upregulated and 3,167 genes were downregulated by more than 2-fold, respectively. The results of functional classification showed that the identified genes were involved in biological pathways including transcription, cell proliferation, the cell cycle, and apoptosis. These gene expression profiles should provide us with further insights into the molecular mechanisms underlying benzene-induced carcinogenesis, including leukemia.
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