Chromatin Redistribution of the DEK Oncoprotein Represses hTERT Transcription in Leukemias
Chromatin Redistribution of the DEK Oncoprotein Represses hTERT Transcription in Leukemias
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DOI：
10.1593/neo.131658
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发表时间：
2014-01-01
期刊：
影响因子：
4.8
通讯作者：
Mortreux, Franck
中科院分区：
文献类型：
--
作者：
Karam, Maroun;Thenoz, Morgan;Mortreux, Franck
虽然已经发现许多因素可以调节hTERT的转录，但其在某些白血病中的抑制机制仍不清楚。我们在这里表明，DEK通过在慢性和急性髓性白血病、慢性淋巴细胞白血病细胞中富集hTERT启动子来抑制hTERT转录，但在hTERT过表达的急性淋巴细胞白血病细胞中则没有。我们从hTERT启动子中分离出DEK，这些启动子与新鲜急性髓性白血病（AML）细胞的核提取物和表达Tax（一种由人类T细胞白血病病毒1型编码的hTERT抑制因子）的细胞孵育。除了募集DEK外，两种已知的hTERT反激活子从hTERT启动子中移位是AML细胞和表达tax的细胞的特征。报告基因和染色质免疫沉淀法可以绘制支持DEK对hTERT转录抑制作用的区域，该区域与DEK启动子关联水平成正比，但与DEK表达水平无关。除了hTERT抑制外，研究还发现，DEK的染色质重分布控制着大约40%的总体转录修饰，包括那些易患癌症的基因。总之，DEK是各种白血病亚型共有的hTERT抑制因子，似乎参与了许多与白血病发生相关的基因的失调。
Although numerous factors have been found to modulate hTERT transcription, the mechanism of its repression in certain leukemias remains unknown. We show here that DEK represses hTERT transcription through its enrichment on the hTERT promoter in cells from chronic and acute myeloid leukemias, chronic lymphocytic leukemia, but not acute lymphocytic leukemias where hTERT is overexpressed. We isolated DEK from the hTERT promoter incubated with nuclear extracts derived from fresh acute myelogenous leukemia (AML) cells and from cells expressing Tax, an hTERT repressor encoded by the human T cell leukemia virus type 1. In addition to the recruitment of DEK, the displacement of two potent known hTERT transactivators from the hTERT promoter characterized both AML cells and Tax-expressing cells. Reporter and chromatin immunoprecipitation assays permitted to map the region that supports the repressive effect of DEK on hTERT transcription, which was proportionate to the level of DEK-promoter association but not with the level of DEK expression. Besides hTERT repression, this context of chromatin redistribution of DEK was found to govern about 40% of overall transcriptional modifications, including those of cancer-prone genes. In conclusion, DEK emerges as an hTERT repressor shared by various leukemia subtypes and seems involved in the deregulation of numerous genes associated with leukemogenesis.