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

被引：67

作者：

Avellino, Roberto ^{[1
]}

Havermans, Marije ^{[1
]}

Erpelinck, Claudia ^{[1
]}

Sanders, Mathijs A. ^{[1
]}

Hoogenboezem, Remco ^{[1
]}

van de Werken, Harmen J. G. ^{[2
,3
,4
]}

Rombouts, Elwin ^{[1
]}

van Lom, Kirsten ^{[1
]}

van Strien, Paulina M. H. ^{[1
]}

Gebhard, Claudia ^{[5
,6
]}

Rehli, Michael ^{[5
,6
]}

Pimanda, John ^{[7
,8
]}

Beck, Dominik ^{[7
,8
]}

Erkeland, Stefan ^{[1
,9
]}

Kuiken, Thijs ^{[10
]}

de Looper, Hans ^{[1
]}

Groeschel, Stefan ^{[1
,11
]}

Touw, Ivo ^{[1
]}

Bindels, Eric ^{[1
]}

Delwel, Ruud ^{[1
]}

机构：

[1] Erasmus Univ, Med Ctr, Dept Hematol, Dr Molewaterpl 50, NL-3015 GE Rotterdam, Netherlands

[2] Erasmus Univ, Med Ctr, Canc Computat Biol Ctr, Rotterdam, Netherlands

[3] Erasmus Univ, Med Ctr, Dept Cell Biol, Rotterdam, Netherlands

[4] Erasmus Univ, Med Ctr, Dept Urol, Rotterdam, Netherlands

[5] Univ Hosp Regensburg, Dept Internal Med 3, Regensburg, Germany

[6] Univ Hosp Regensburg, Regensburg Ctr Intervent Immunol, Regensburg, Germany

[7] Univ New S Wales, Prince Wales Clin Sch, Sydney, NSW, Australia

[8] Univ New S Wales, Lowy Canc Res Ctr, Sydney, NSW, Australia

[9] Erasmus Univ, Dept Immunol, Med Ctr, POB 1738, NL-3000 DR Rotterdam, Netherlands

[10] Erasmus Univ, Med Ctr, Dept Virosci, Rotterdam, Netherlands

[11] DKFZ, Natl Ctr Tumor Dis, Dept Translat Oncol, Heidelberg, Germany

来源：

BLOOD | 2016年 / 127卷 / 24期

关键词：

FACTOR-C/EBP-ALPHA; TRANSCRIPTION FACTORS; DEVELOPMENTAL ENHANCERS; CHROMATIN INTERACTIONS; SELF-RENEWAL; HUMAN GENOME; EXPRESSION; LEUKEMIA; COMMITMENT; BINDING;

D O I：

10.1182/blood-2016-01-695759

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

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.

引用

页码：2991 / 3003

页数：13

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