An autonomous CEBPA enhancer specific for myeloid-lineage priming and neutrophilic differentiation.

Abstract:

:Neutrophilic differentiation is dependent on CCAAT enhancer-binding protein α (C/EBPα), a transcription factor expressed in multiple organs including the bone marrow. Using functional genomic technologies in combination with clustered regularly-interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 genome editing and in vivo mouse modeling, we show that CEBPA is located in a 170-kb topological-associated domain that contains 14 potential enhancers. Of these, 1 enhancer located +42 kb from CEBPA is active and engages with the CEBPA promoter in myeloid cells only. Germ line deletion of the homologous enhancer in mice in vivo reduces Cebpa levels exclusively in hematopoietic stem cells (HSCs) and myeloid-primed progenitor cells leading to severe defects in the granulocytic lineage, without affecting any other Cebpa-expressing organ studied. The enhancer-deleted progenitor cells lose their myeloid transcription program and are blocked in differentiation. Deletion of the enhancer also causes loss of HSC maintenance. We conclude that a single +42-kb enhancer is essential for CEBPA expression in myeloid cells only.

journal_name

Blood

journal_title

Blood

authors

Avellino R,Havermans M,Erpelinck C,Sanders MA,Hoogenboezem R,van de Werken HJ,Rombouts E,van Lom K,van Strien PM,Gebhard C,Rehli M,Pimanda J,Beck D,Erkeland S,Kuiken T,de Looper H,Gröschel S,Touw I,Bindels E,Delwel

doi

10.1182/blood-2016-01-695759

subject

Has Abstract

pub_date

2016-06-16 00:00:00

pages

2991-3003

issue

24

eissn

0006-4971

issn

1528-0020

pii

blood-2016-01-695759

journal_volume

127

pub_type

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