Avellino, Roberto and Havermans, Marije and Erpelinck, Claudia and Sanders, Mathijs A. and Hoogenboezem, Remco and van de Werken, Harmen J. G. and Rombouts, Elwin and van Lom, Kirsten and van Strien, Paulina M. H. and Gebhard, Claudia and Rehli, Michael and Pimanda, John and Beck, Dominik and Erkeland, Stefan and Kuiken, Thijs and de Looper, Hans and Groeschel, Stefan and Touw, Ivo and Bindels, Eric and Delwel, Ruud (2016) An autonomous CEBPA enhancer specific for myeloid-lineage priming and neutrophilic differentiation. BLOOD, 127 (24). pp. 2991-3003. ISSN 0006-4971, 1528-0020
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | FACTOR-C/EBP-ALPHA; TRANSCRIPTION FACTORS; DEVELOPMENTAL ENHANCERS; CHROMATIN INTERACTIONS; SELF-RENEWAL; HUMAN GENOME; EXPRESSION; LEUKEMIA; COMMITMENT; BINDING; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 08 Apr 2019 09:15 |
| Last Modified: | 08 Apr 2019 09:15 |
| URI: | https://pred.uni-regensburg.de/id/eprint/3760 |
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