Post transcriptional control of the epigenetic stem cell regulator PLZF by sirtuin and HDAC deacetylases

Epigenetics & Chromatin

Fabien Guidez²  Jonathan D. Licht³  Tony Kouzarides⁵  Christine Chomienne²  Arthur Zelent¹  Lise Coste-Sarguet²  Emma Langley⁴  Laetitia Durand²  Melanie J. McConnell³ 

[1] Division of Hemato-oncology, Miller School of Medicine, Miami 33136, FL, USA;INSERM UMRS-1131, Institut universitaire d’Hématologie, Université Paris Diderot, 1 avenue Claude Vellefaux, hôpital Saint-Louis, Paris, 75010, France;Division of Hematology/Oncology, Mount Sinai School of Medicine, New York 10029, NY, USA;Biogen Idec, San Diego 92122, CA, USA;Wellcome Institute/Cancer Research UK, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK

关键词: Epigenetic;    Deacetylation;    DNA methylation;    Repression;   

Others  :  1227237
DOI  :  10.1186/s13072-015-0030-8

 received in 2015-07-08, accepted in 2015-09-14,  发布年份 2015

【 摘 要 】

Background

The transcriptional repressor promyelocytic leukemia zinc finger protein (PLZF) is critical for the regulation of normal stem cells maintenance by establishing specific epigenetic landscape. We have previously shown that CBP/p300 acetyltransferase induces PLZF acetylation in order to increase its deoxynucleotidic acid (DNA) binding activity and to enhance its epigenetic function (repression of PLZF target genes). However, how PLZF is inactivated is not yet understood.

Results

In this study, we demonstrate that PLZF is deacetylated by both histone deacetylase 3 and the NAD+ dependent deacetylase silent mating type information regulation 2 homolog 1 (SIRT1). Unlike other PLZF-interacting deacetylases, these two proteins interact with the zinc finger domain of PLZF, where the activating CBP/p300 acetylation site was previously described, inducing deacetylation of lysines 647/650/653. Overexpression of histone deacetylase 3 (HDAC3) and SIRT1 is associated with loss of PLZF DNA binding activity and decreases PLZF transcriptional repression. As a result, the chromatin status of the promoters of PLZF target genes, involved in oncogenesis, shift from a heterochromatin to an open euchromatin environment leading to gene expression even in the presence of PLZF.

Conclusions

Consequently, SIRT1 and HDAC3 mediated-PLZF deacetylation provides for rapid control and fine-tuning of PLZF activity through post-transcriptional modification to regulate gene expression and cellular homeostasis.

【 授权许可】

   
2015 McConnell et al.

【 图 表 】

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