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

Maximilian Witzel, Daniel Petersheim, Yanxin Fan, Ehsan Bahrami, Tomas Racek, Meino Rohlfs, Jacek Puchałka, Christian Mertes, Julien Gagneur, Christoph Ziegenhain, Wolfgang Enard, Asbjørg Stray-Pedersen, Peter D. 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. Schäffer, Christoph Klein

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34 Citations (Scopus)

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 CEBPIϵ 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.

Original languageEnglish
Pages (from-to)742-752
Number of pages11
JournalNature Genetics
Volume49
Issue number5
DOIs
Publication statusPublished - 1 May 2017

Keywords

  • gene regulation
  • immunological deficiency syndromes
  • myelodysplastic syndrome
  • translational research

Cite this

Witzel, M., Petersheim, D., Fan, Y., Bahrami, E., Racek, T., Rohlfs, M., Puchałka, J., Mertes, C., Gagneur, J., Ziegenhain, C., Enard, W., Stray-Pedersen, A., Arkwright, P. D., Abboud, M. R., Pazhakh, V., Lieschke, G. J., Krawitz, P. M., Dahlhoff, M., Schneider, M. R., ... Klein, C. (2017). Chromatin-remodeling factor SMARCD2 regulates transcriptional networks controlling differentiation of neutrophil granulocytes. Nature Genetics, 49(5), 742-752. https://doi.org/10.1038/ng.3833