title: Chromatin-remodeling factor SMARCD2 regulates transcriptional networks controlling differentiation of neutrophil granulocytes.
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.
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.|Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Witzel
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Petersheim
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Bahrami
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Tomas
authors.initials: T
authors.lastname: Racek
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Meino
authors.initials: M
authors.lastname: Rohlfs
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Jacek
authors.initials: J
authors.lastname: Puchałka
authors.affiliation: Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Christian
authors.identifier: http://orcid.org/0000-0002-1091-205X
authors.initials: C
authors.lastname: Mertes
authors.affiliation: Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany.|Department of Informatics, Technical University of Munich, Munich, Germany.
authors.forename: Julien
authors.initials: J
authors.lastname: Gagneur
authors.affiliation: Anthropology and Human Genomics, Department of Biology II, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Ziegenhain
authors.affiliation: Anthropology and Human Genomics, Department of Biology II, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Wolfgang
authors.identifier: http://orcid.org/0000-0002-4056-0550
authors.initials: W
authors.lastname: Enard
authors.affiliation: Norwegian National Unit for Newborn Screening, Oslo University Hospital, Oslo, Norway.
authors.forename: Asbjørg
authors.initials: A
authors.lastname: Stray-Pedersen
authors.affiliation: Department of Paediatric Allergy and Immunology, University of Manchester, Royal Manchester Children's Hospital, Manchester, UK.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Arkwright
authors.affiliation: Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
authors.forename: Miguel R
authors.initials: MR
authors.lastname: Abboud
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.
authors.forename: Vahid
authors.initials: V
authors.lastname: Pazhakh
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.
authors.forename: Graham J
authors.identifier: http://orcid.org/0000-0003-0325-798X
authors.initials: GJ
authors.lastname: Lieschke
authors.affiliation: Medical Genetics and Human Genetic, Charite University Hospital, Berlin, Germany.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Krawitz
authors.affiliation: Molecular Animal Breeding and Biotechnology, Gene Center Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Maik
authors.initials: M
authors.lastname: Dahlhoff
authors.affiliation: Molecular Animal Breeding and Biotechnology, Gene Center Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Marlon R
authors.initials: MR
authors.lastname: Schneider
authors.affiliation: Molecular Animal Breeding and Biotechnology, Gene Center Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.affiliation: Pathology Institute, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Horny
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Schmidt
authors.affiliation: National Center for Biotechnology Information, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA.
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.|Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D053263:Gene Regulatory Networks; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism*; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics*; D015027:Zebrafish
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C491651:SMARCD2 protein, human; D014157:Transcription Factors