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Nucleic Acids Res. 2016 May 5;44(8):3567-85. doi: 10.1093/nar/gkv1475. Epub 2015 Dec 15.

Dynamic recruitment of Ets1 to both nucleosome-occupied and -depleted enhancer regions mediates a transcriptional program switch during early T-cell differentiation.

Author information

1
CIML CNRS UMR7280, Case 906, Campus de Luminy, Marseille F-13009, France CIML INSERM U1104, Case 906, Campus de Luminy, Marseille F-13009, France Aix-Marseille University, 58 Boulevard Charles Livon, Marseille F-13284, France Inserm U1090, Technological Advances for Genomics and Clinics (TAGC), Marseille F-13009, France Aix-Marseille University UMR-S 1090, TAGC, Marseille F-13009, France.
2
Institut de Génétique Moléculaire de Montpellier, CNRS UMR5535, 1919 Route de Mende, Montpellier F-34293, France.
3
CIML CNRS UMR7280, Case 906, Campus de Luminy, Marseille F-13009, France CIML INSERM U1104, Case 906, Campus de Luminy, Marseille F-13009, France Aix-Marseille University, 58 Boulevard Charles Livon, Marseille F-13284, France.
4
Inserm U1090, Technological Advances for Genomics and Clinics (TAGC), Marseille F-13009, France Aix-Marseille University UMR-S 1090, TAGC, Marseille F-13009, France.
5
Centre Nacional D'Anàlisi Genòmica, Parc Científic de Barcelona, Baldiri i Reixac 4, Barcelona ES-08028, Spain.
6
INSERM UMR 1126 Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris F-75475, France.
7
Inserm U1090, Technological Advances for Genomics and Clinics (TAGC), Marseille F-13009, France Aix-Marseille University UMR-S 1090, TAGC, Marseille F-13009, France salvatore.spicuglia@inserm.fr.
8
Institut de Génétique Moléculaire de Montpellier, CNRS UMR5535, 1919 Route de Mende, Montpellier F-34293, France jean-christophe.andrau@igmm.cnrs.fr.

Abstract

Ets1 is a sequence-specific transcription factor that plays an important role during hematopoiesis, and is essential for the transition of CD4(-)/CD8(-) double negative (DN) to CD4(+)/CD8(+) double positive (DP) thymocytes. Using genome-wide and functional approaches, we investigated the binding properties, transcriptional role and chromatin environment of Ets1 during this transition. We found that while Ets1 binding at distal sites was associated with active genes at both DN and DP stages, its enhancer activity was attained at the DP stage, as reflected by levels of the core transcriptional hallmarks H3K4me1/3, RNA Polymerase II and eRNA. This dual, stage-specific ability reflected a switch from non-T hematopoietic toward T-cell specific gene expression programs during the DN-to-DP transition, as indicated by transcriptome analyses of Ets1(-/-) thymic cells. Coincidentally, Ets1 associates more specifically with Runx1 in DN and with TCF1 in DP cells. We also provide evidence that Ets1 predominantly binds distal nucleosome-occupied regions in DN and nucleosome-depleted regions in DP. Finally and importantly, we demonstrate that Ets1 induces chromatin remodeling by displacing H3K4me1-marked nucleosomes. Our results thus provide an original model whereby the ability of a transcription factor to bind nucleosomal DNA changes during differentiation with consequences on its cognate enhancer activity.

PMID:
26673693
PMCID:
PMC4856961
DOI:
10.1093/nar/gkv1475
[Indexed for MEDLINE]
Free PMC Article

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