端粒酶逆转录酶
端粒酶
生物
染色质
心理压抑
表观遗传学
转录因子
发起人
DNA甲基化
抑制因子
癌症研究
分子生物学
细胞生物学
基因
基因表达
遗传学
作者
Abdulkader Azouz,Yue Wu,Josette Hillion,Ilona Tárkányi,A. Karniguian,J. Aradi,Michele Lanotte,Chen Gq,M. Fawaz Chehna,Évelyne Ségal-Bendirdjian
出处
期刊:Leukemia
[Springer Nature]
日期:2010-01-14
卷期号:24 (3): 613-622
被引量:29
摘要
The expression of hTERT gene, encoding the catalytic subunit of telomerase, is a feature of most cancer cells. Changes in the chromatin environment of its promoter and binding of transcriptional factors have been reported in differentiating cells when its transcription is repressed. However, it is not clear whether these changes are directly involved in this repression or only linked to differentiation. In a maturation-resistant acute promyelocytic leukemia (APL) cell line (NB4-LR1), we have previously identified a new pathway of retinoid-induced hTERT repression independent of differentiation. Using a variant of this cell line (NB4-LR1SFD), which resists to this repression, we show that although distinct patterns of histone modifications and transcription factor binding at the proximal domain of hTERT gene promoter could concur to modulate its expression, this region is not sufficient to the on/off switch of hTERT by retinoids. DNA methylation analysis of the hTERT promoter led to the identification of two distinct functional domains, a proximal one, fully unmethylated in both cell lines, and a distal one, significantly methylated in NB4-LR1SFD cells, whose methylation was further re-enforced by retinoid treatment. Interestingly, we showed that the binding to this distal domain of a known hTERT repressor, WT1, was defective only in NB4-LR1SFD cells. We propose that epigenetic modifications targeting this distal region could modulate the binding of hTERT repressors and account either for hTERT reactivation and resistance to retinoid-induced hTERT downregulation.
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