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

Nat Genet. 2017 May;49(5):742-752. doi: 10.1038/ng.3833.

Maximilian Witzel ¹ ², Daniel Petersheim ¹, Yanxin Fan ¹, Ehsan Bahrami ¹, Tomas Racek ¹, Meino Rohlfs ¹, Jacek Puchałka ¹, Christian Mertes ², Julien Gagneur ² ³, Christoph Ziegenhain ⁴, Wolfgang Enard ⁴, Asbjørg Stray-Pedersen ⁵, Peter D Arkwright ⁶, Miguel R Abboud ⁷, Vahid Pazhakh ⁸, Graham J Lieschke ⁸, Peter M Krawitz ⁹, Maik Dahlhoff ¹⁰, Marlon R Schneider ¹⁰, Eckhard Wolf ¹⁰, Hans-Peter Horny ¹¹, Heinrich Schmidt ¹, Alejandro A Schäffer ¹², Christoph Klein ¹ ²

Affiliations

1 Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
2 Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany.
3 Department of Informatics, Technical University of Munich, Munich, Germany.
4 Anthropology and Human Genomics, Department of Biology II, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany.
5 Norwegian National Unit for Newborn Screening, Oslo University Hospital, Oslo, Norway.
6 Department of Paediatric Allergy and Immunology, University of Manchester, Royal Manchester Children's Hospital, Manchester, UK.
7 Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
8 Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.
9 Medical Genetics and Human Genetic, Charite University Hospital, Berlin, Germany.
10 Molecular Animal Breeding and Biotechnology, Gene Center Ludwig-Maximilians-Universität München, Munich, Germany.
11 Pathology Institute, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
12 National Center for Biotechnology Information, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA.

PMID: 28369036 DOI: 10.1038/ng.3833

Abstract

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 CEBPɛ 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.

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