Gene-body hypermethylation controlled cryptic promoter and miR26A1-dependent EZH2 regulation of TET1 gene activity in chronic lymphocytic leukemia

被引:6
作者
Kopparapu, Pradeep Kumar [1 ]
Morsy, Mohammad Hamdy Abdelrazak [1 ]
Kanduri, Chandrasekhar [2 ]
Kanduri, Meena [1 ]
机构
[1] Gothenburg Univ, Sahlgrenska Acad, Inst Biomed, Dept Clin Chem & Transfus Med, Gothenburg, Sweden
[2] Gothenburg Univ, Sahlgrenska Acad, Inst Biomed, Dept Med Biochem & Cell Biol, Gothenburg, Sweden
基金
瑞典研究理事会;
关键词
gene-body hypermethylation; chronic lymphocytic leukemia; cryptic promoters; EZH2 and TET1 gene; MANTLE CELL LYMPHOMA; INTRAGENIC DNA METHYLATION; MLL-REARRANGED LEUKEMIA; TUMOR-SUPPRESSOR; IN-VITRO; EXPRESSION; CANCER; INHIBITORS; PROTEINS; DISEASE;
D O I
10.18632/oncotarget.20668
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The Ten-eleven-translocation 1 (TET1) protein is a member of dioxygenase protein family that catalyzes the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine. TET1 is differentially expressed in many cancers, including leukemia. However, very little is known about mechanism behind TET1 deregulation. Previously, by characterizing global methylation patterns in CLL patients using MBD-seq, we found TET1 as one of the differentially methylated regions with gene-body hypermethylation. Herein, we characterize mechanisms that control TET1 gene activity at the transcriptional level. We show that treatment of CLL cell lines with 5-aza 2'-deoxycytidine (DAC) results in the activation of miR26A1, which causes decrease in both mRNA and protein levels of EZH2, which in turn results in the decreased occupancy of EZH2 over the TET1 promoter and consequently the loss of TET1 expression. In addition, DAC treatment also leads to the activation of antisense transcription overlapping the TET1 gene from a cryptic promoter, located in the hypermethylated intronic region. Increased expression of intronic transcripts correlates with decreased TET1 promoter activity through the loss of RNA Pol II occupancy. Thus, our data demonstrate that TET1 gene activation in CLL depends on miR26A1 regulated EZH2 binding at the TET1 promoter and silencing of novel cryptic promoter by gene-body hypermethylation.
引用
收藏
页码:77595 / 77608
页数:14
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