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Epigenetic plasticity of hTERT gene promoter determines retinoid capacity to repress telomerase in maturation-resistant acute promyelocytic leukemia cells

Abdulkader Azouz, Y-L Wu, J Hillion, I Tarkanyi, A Karniguian, J Aradi, M Lanotte, G-Q Chen, M Chehna, E Ségal-Bendirdjian

Leukemia, Volume: 24, Issue: 3, Pages: 613 - 622

Swansea University Author: Abdulkader Azouz

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DOI (Published version): 10.1038/leu.2009.283

Abstract

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 n...

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Published in: Leukemia
ISSN: 0887-6924 1476-5551
Published: Springer Science and Business Media LLC 2010
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URI: https://cronfa.swan.ac.uk/Record/cronfa12648
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spelling 2022-11-02T13:54:10.6078082 v2 12648 2012-09-11 Epigenetic plasticity of hTERT gene promoter determines retinoid capacity to repress telomerase in maturation-resistant acute promyelocytic leukemia cells e94d1fcbea6b2f7761bd64ec02dfc8cb Abdulkader Azouz Abdulkader Azouz true false 2012-09-11 PMSC 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. Journal Article Leukemia 24 3 613 622 Springer Science and Business Media LLC 0887-6924 1476-5551 1 3 2010 2010-03-01 10.1038/leu.2009.283 COLLEGE NANME Medicine COLLEGE CODE PMSC Swansea University 2022-11-02T13:54:10.6078082 2012-09-11T12:09:29.5131735 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Abdulkader Azouz 1 Y-L Wu 2 J Hillion 3 I Tarkanyi 4 A Karniguian 5 J Aradi 6 M Lanotte 7 G-Q Chen 8 M Chehna 9 E Ségal-Bendirdjian 10
title Epigenetic plasticity of hTERT gene promoter determines retinoid capacity to repress telomerase in maturation-resistant acute promyelocytic leukemia cells
spellingShingle Epigenetic plasticity of hTERT gene promoter determines retinoid capacity to repress telomerase in maturation-resistant acute promyelocytic leukemia cells
Abdulkader Azouz
title_short Epigenetic plasticity of hTERT gene promoter determines retinoid capacity to repress telomerase in maturation-resistant acute promyelocytic leukemia cells
title_full Epigenetic plasticity of hTERT gene promoter determines retinoid capacity to repress telomerase in maturation-resistant acute promyelocytic leukemia cells
title_fullStr Epigenetic plasticity of hTERT gene promoter determines retinoid capacity to repress telomerase in maturation-resistant acute promyelocytic leukemia cells
title_full_unstemmed Epigenetic plasticity of hTERT gene promoter determines retinoid capacity to repress telomerase in maturation-resistant acute promyelocytic leukemia cells
title_sort Epigenetic plasticity of hTERT gene promoter determines retinoid capacity to repress telomerase in maturation-resistant acute promyelocytic leukemia cells
author_id_str_mv e94d1fcbea6b2f7761bd64ec02dfc8cb
author_id_fullname_str_mv e94d1fcbea6b2f7761bd64ec02dfc8cb_***_Abdulkader Azouz
author Abdulkader Azouz
author2 Abdulkader Azouz
Y-L Wu
J Hillion
I Tarkanyi
A Karniguian
J Aradi
M Lanotte
G-Q Chen
M Chehna
E Ségal-Bendirdjian
format Journal article
container_title Leukemia
container_volume 24
container_issue 3
container_start_page 613
publishDate 2010
institution Swansea University
issn 0887-6924
1476-5551
doi_str_mv 10.1038/leu.2009.283
publisher Springer Science and Business Media LLC
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 0
active_str 0
description 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.
published_date 2010-03-01T03:14:34Z
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score 11.017776

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