Characterisation of genome-wide PLZF/RARA target genes.

The PLZF/RARA fusion protein generated by the t(11;17)(q23;q21) translocation in acute promyelocytic leukaemia (APL) is believed to act as an oncogenic transcriptional regulator recruiting epigenetic factors to genes important for its transforming potential. However, molecular mechanisms associated...

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Autores principales:	Salvatore Spicuglia, Christelle Vincent-Fabert, Touati Benoukraf, Guillaume Tibéri, Andrew J Saurin, Joaquin Zacarias-Cabeza, David Grimwade, Ken Mills, Boris Calmels, François Bertucci, Michael Sieweke, Pierre Ferrier, Estelle Duprez
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/036763c1e99d4a398ec92fd73ef0dbbb
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spelling	oai:doaj.org-article:036763c1e99d4a398ec92fd73ef0dbbb2021-11-04T06:08:14ZCharacterisation of genome-wide PLZF/RARA target genes.1932-620310.1371/journal.pone.0024176https://doaj.org/article/036763c1e99d4a398ec92fd73ef0dbbb2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21949697/?tool=EBIhttps://doaj.org/toc/1932-6203The PLZF/RARA fusion protein generated by the t(11;17)(q23;q21) translocation in acute promyelocytic leukaemia (APL) is believed to act as an oncogenic transcriptional regulator recruiting epigenetic factors to genes important for its transforming potential. However, molecular mechanisms associated with PLZF/RARA-dependent leukaemogenesis still remain unclear.We searched for specific PLZF/RARA target genes by ChIP-on-chip in the haematopoietic cell line U937 conditionally expressing PLZF/RARA. By comparing bound regions found in U937 cells expressing endogenous PLZF with PLZF/RARA-induced U937 cells, we isolated specific PLZF/RARA target gene promoters. We next analysed gene expression profiles of our identified target genes in PLZF/RARA APL patients and analysed DNA sequences and epigenetic modification at PLZF/RARA binding sites. We identify 413 specific PLZF/RARA target genes including a number encoding transcription factors involved in the regulation of haematopoiesis. Among these genes, 22 were significantly down regulated in primary PLZF/RARA APL cells. In addition, repressed PLZF/RARA target genes were associated with increased levels of H3K27me3 and decreased levels of H3K9K14ac. Finally, sequence analysis of PLZF/RARA bound sequences reveals the presence of both consensus and degenerated RAREs as well as enrichment for tissue-specific transcription factor motifs, highlighting the complexity of targeting fusion protein to chromatin. Our study suggests that PLZF/RARA directly targets genes important for haematopoietic development and supports the notion that PLZF/RARA acts mainly as an epigenetic regulator of its direct target genes.Salvatore SpicugliaChristelle Vincent-FabertTouati BenoukrafGuillaume TibériAndrew J SaurinJoaquin Zacarias-CabezaDavid GrimwadeKen MillsBoris CalmelsFrançois BertucciMichael SiewekePierre FerrierEstelle DuprezPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 9, p e24176 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Salvatore Spicuglia Christelle Vincent-Fabert Touati Benoukraf Guillaume Tibéri Andrew J Saurin Joaquin Zacarias-Cabeza David Grimwade Ken Mills Boris Calmels François Bertucci Michael Sieweke Pierre Ferrier Estelle Duprez Characterisation of genome-wide PLZF/RARA target genes.
description	The PLZF/RARA fusion protein generated by the t(11;17)(q23;q21) translocation in acute promyelocytic leukaemia (APL) is believed to act as an oncogenic transcriptional regulator recruiting epigenetic factors to genes important for its transforming potential. However, molecular mechanisms associated with PLZF/RARA-dependent leukaemogenesis still remain unclear.We searched for specific PLZF/RARA target genes by ChIP-on-chip in the haematopoietic cell line U937 conditionally expressing PLZF/RARA. By comparing bound regions found in U937 cells expressing endogenous PLZF with PLZF/RARA-induced U937 cells, we isolated specific PLZF/RARA target gene promoters. We next analysed gene expression profiles of our identified target genes in PLZF/RARA APL patients and analysed DNA sequences and epigenetic modification at PLZF/RARA binding sites. We identify 413 specific PLZF/RARA target genes including a number encoding transcription factors involved in the regulation of haematopoiesis. Among these genes, 22 were significantly down regulated in primary PLZF/RARA APL cells. In addition, repressed PLZF/RARA target genes were associated with increased levels of H3K27me3 and decreased levels of H3K9K14ac. Finally, sequence analysis of PLZF/RARA bound sequences reveals the presence of both consensus and degenerated RAREs as well as enrichment for tissue-specific transcription factor motifs, highlighting the complexity of targeting fusion protein to chromatin. Our study suggests that PLZF/RARA directly targets genes important for haematopoietic development and supports the notion that PLZF/RARA acts mainly as an epigenetic regulator of its direct target genes.
format	article
author	Salvatore Spicuglia Christelle Vincent-Fabert Touati Benoukraf Guillaume Tibéri Andrew J Saurin Joaquin Zacarias-Cabeza David Grimwade Ken Mills Boris Calmels François Bertucci Michael Sieweke Pierre Ferrier Estelle Duprez
author_facet	Salvatore Spicuglia Christelle Vincent-Fabert Touati Benoukraf Guillaume Tibéri Andrew J Saurin Joaquin Zacarias-Cabeza David Grimwade Ken Mills Boris Calmels François Bertucci Michael Sieweke Pierre Ferrier Estelle Duprez
author_sort	Salvatore Spicuglia
title	Characterisation of genome-wide PLZF/RARA target genes.
title_short	Characterisation of genome-wide PLZF/RARA target genes.
title_full	Characterisation of genome-wide PLZF/RARA target genes.
title_fullStr	Characterisation of genome-wide PLZF/RARA target genes.
title_full_unstemmed	Characterisation of genome-wide PLZF/RARA target genes.
title_sort	characterisation of genome-wide plzf/rara target genes.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/036763c1e99d4a398ec92fd73ef0dbbb
work_keys_str_mv	AT salvatorespicuglia characterisationofgenomewideplzfraratargetgenes AT christellevincentfabert characterisationofgenomewideplzfraratargetgenes AT touatibenoukraf characterisationofgenomewideplzfraratargetgenes AT guillaumetiberi characterisationofgenomewideplzfraratargetgenes AT andrewjsaurin characterisationofgenomewideplzfraratargetgenes AT joaquinzacariascabeza characterisationofgenomewideplzfraratargetgenes AT davidgrimwade characterisationofgenomewideplzfraratargetgenes AT kenmills characterisationofgenomewideplzfraratargetgenes AT boriscalmels characterisationofgenomewideplzfraratargetgenes AT francoisbertucci characterisationofgenomewideplzfraratargetgenes AT michaelsieweke characterisationofgenomewideplzfraratargetgenes AT pierreferrier characterisationofgenomewideplzfraratargetgenes AT estelleduprez characterisationofgenomewideplzfraratargetgenes
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Characterisation of genome-wide PLZF/RARA target genes.

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