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

Roberto Avellino, Marije Havermans, Claudia Erpelinck - Verschueren, Mathijs Sanders, Remco Hoogenboezem, Harmen van de Werken, J Chikhovskaya, Kirsten van Lom, Paulette Strien, C Gebhard, M Rehli, J Pimanda, D Beck, Stefan Erkeland, Thijs Kuiken, Hans de Looper, SM Groschel, Ivo Touw, Eric Bindels, Ruud Delwel

Research output: Contribution to journalArticleAcademicpeer-review

53 Citations (Scopus)

Abstract

Neutrophilic differentiation is dependent on CCAAT enhancer-binding protein a (C/EBP alpha), 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 142 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.
Original languageUndefined/Unknown
Pages (from-to)2991-3003
Number of pages13
JournalBlood
Volume127
Issue number24
DOIs
Publication statusPublished - 2016

Research programs

  • EMC MM-02-41-03
  • EMC MM-02-72-02
  • EMC MM-03-49-01
  • EMC MM-04-27-01

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