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.
PP-29-100 Background/Aims: Even though the exposure to benzene has been linked to variety of cancers including leukemia, the detailed molecular mechanism of carcinogenesis by benzene remains unidentified. We investigated the effects of benzene on differential gene expression in leukemia. Methods: After leukemia cell (K562) were cultured in RPMI media with 10 mM benzene, RNA extraction, and nucleosome extraction. To analyze the gene expression profiles, using 41,000 human whole genome cDNA microarray, western blot analysis. Results: We initially identified 154 gene altered by benzene treatment. Of these, 88 genes were upregulated and 66 genes were down regulated more than 6 fold, respectively. Functional classification revealed that identified genes were involved in transcription, cell proliferation, cell cycle, and apoptosis. Additionally, we have identified that benzene treatment modified histone modifications including histone H3 and H4 acetylation status in K562 cells. Conclusion: These gene expression profiles should provide further understanding of the molecular mechanism of benzene-induced leukemogenesis.
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