Chromatin-remodeling factor SMARCD2 regulates transcriptional networks controlling differentiation of neutrophil granulocytes

被引：84

作者：

Witzel, Maximilian ^{[1
,2
]}

Petersheim, Daniel ^{[1
]}

Fan, Yanxin ^{[1
]}

Bahrami, Ehsan ^{[1
]}

Racek, Tomas ^{[1
]}

Rohlfs, Meino ^{[1
]}

Puchalka, Jacek ^{[1
]}

Mertes, Christian ^{[2
]}

Gagneur, Julien ^{[2
,3
]}

Ziegenhain, Christoph ^{[4
]}

Enard, Wolfgang ^{[4
]}

Stray-Pedersen, Asbjorg ^{[5
]}

Arkwright, Peter D. ^{[6
]}

Abboud, Miguel R. ^{[7
]}

Pazhakh, Vahid ^{[8
]}

Lieschke, Graham J. ^{[8
]}

Krawitz, Peter M. ^{[9
]}

Dahlhoff, Maik ^{[10
]}

Schneider, Marlon R. ^{[10
]}

Wolf, Eckhard ^{[10
]}

Horny, Hans-Peter ^{[11
]}

Schmidt, Heinrich ^{[1
]}

Schaffer, Alejandro A. ^{[12
]}

Klein, Christoph ^{[1
,2
]}

机构：

[1] Ludwig Maximilians Univ Munchen, Dr von Hauner Childrens Hosp, Dept Pediat, Munich, Germany

[2] Ludwig Maximilians Univ Munchen, Gene Ctr, Munich, Germany

[3] Tech Univ Munich, Dept Informat, Munich, Germany

[4] Ludwig Maximilians Univ Munchen, Fac Biol, Dept Biol 2, Anthropol & Human Genom, Munich, Germany

[5] Oslo Univ Hosp, Norwegian Natl Unit Newborn Screening, Oslo, Norway

[6] Univ Manchester, Royal Manchester Childrens Hosp, Dept Paediat Allergy & Immunol, Manchester, Lancs, England

[7] Amer Univ Beirut, Med Ctr, Dept Pediat & Adolescent Med, Beirut, Lebanon

[8] Monash Univ, Australian Regenerat Med Inst, Clayton, Vic, Australia

[9] Charite, Med Genet & Human Genet, Berlin, Germany

[10] Ludwig Maximilians Univ Munchen, Gene Ctr, Mol Anim Breeding & Biotechnol, Munich, Germany

[11] Ludwig Maximilians Univ Munchen, Fac Med, Inst Pathol, Munich, Germany

[12] US Natl Inst Hlth, Natl Ctr Biotechnol Informat, US Dept HHS, Bethesda, MD USA

来源：

NATURE GENETICS | 2017年 / 49卷 / 05期

基金：

欧洲研究理事会; 澳大利亚国家健康与医学研究理事会; 美国国家卫生研究院; 英国医学研究理事会;

关键词：

BINDING-PROTEIN-EPSILON; GRANULE DEFICIENCY; C/EBP-EPSILON; MUTATIONAL ANALYSIS; EXPRESSION; SEQUENCE; SWI/SNF; GENE; LEUKEMIA; MODEL;

D O I：

10.1038/ng.3833

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We identify SMARCD2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily D, member 2), also known as BAF60b (BRG1/Brahma-associated factor 60b), as a critical regulator of myeloid differentiation in humans, mice, and zebrafish. Studying patients from three unrelated pedigrees characterized by neutropenia, specific granule deficiency, myelodysplasia with excess of blast cells, and various developmental aberrations, we identified three homozygous loss-of-function mutations in SMARCD2. Using mice and zebrafish as model systems, we showed that SMARCD2 controls early steps in the differentiation of myeloid-erythroid progenitor cells. In vitro, SMARCD2 interacts with the transcription factor CEBPe and controls expression of neutrophil proteins stored in specific granules. Defective expression of SMARCD2 leads to transcriptional and chromatin changes in acute myeloid leukemia (AML) human promyelocytic cells. In summary, SMARCD2 is a key factor controlling myelopoiesis and is a potential tumor suppressor in leukemia.

引用

页码：742 / +

页数：14

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