Chromatin remodelling factor SMARCD2 regulates transcriptional networks controlling differentiation of neutrophil granulocytes

Maximilian Witzel, Daniel Petersheim, Yanxin Fan, Ehsan Bahrami, Tomas Racek, Meino Rohlfs, Jacek Puchalka, Christian Mertes, Julien Gagneur, Christoph Ziegenhain, Wolfgang Enard, A. Stray-Pedersen, Peter Arkwright, Miguel R. Abboud, Vahid Pazhakh, Graham J. Lieschke, Peter M. Krawitz, Maik Dahlhoff, Marlon R. Schneider, Eckhard WolfHans Peter Horny, Heinrich Schmidt, Alejandro A. Schaffer, Christoph Klein

Research output: Contribution to journalArticlepeer-review

456 Downloads (Pure)

Abstract

Differentiation of hematopoietic stem cells follows a hierarchical program of transcription factor regulated events1-3. Early myeloid cell differentiation is dependent on PU.1 and CEBPA (CCAAT/enhancer binding protein alpha), late myeloid differentiation is orchestrated by CEBPE (CCAAT/enhancer binding protein epsilon)4. The influence of SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodelling factors as novel master regulators of hematopoietic differentiation is only beginning to be explored3,5,6. Here, we identify SMARCD2 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d, member 2) 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 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 a potential tumor suppressor in leukemia.
Original languageEnglish
Pages (from-to)742-752
Number of pages11
JournalNature Genetics
Volume49
Issue number5
Early online date3 Apr 2017
DOIs
Publication statusPublished - May 2017

Keywords

  • Hematopoiesis
  • primary immunodeficiency disorder
  • SWI/SNF complex
  • specific granule deficiency
  • leukemogenesis
  • congenital neutropenia

Fingerprint

Dive into the research topics of 'Chromatin remodelling factor SMARCD2 regulates transcriptional networks controlling differentiation of neutrophil granulocytes'. Together they form a unique fingerprint.

Cite this