ZFIN ID: ZDB-PUB-170404-9
Chromatin-remodeling factor SMARCD2 regulates transcriptional networks controlling differentiation of neutrophil granulocytes
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., Wolf, E., Horny, H.P., Schmidt, H., Schäffer, A.A., Klein, C.
Date: 2017
Source: Nature Genetics   49(5): 742-752 (Journal)
Registered Authors: Lieschke, Graham J., Pazhakh, Vahid
Keywords: Gene regulation, Immunological deficiency syndromes, Myelodysplastic syndrome, Translational research
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Base Sequence
  • Cell Differentiation/genetics*
  • Cell Line, Tumor
  • Chromatin Assembly and Disassembly
  • DNA Mutational Analysis
  • Family Health
  • Female
  • Gene Regulatory Networks*
  • Humans
  • Leukemia, Promyelocytic, Acute/genetics
  • Leukemia, Promyelocytic, Acute/pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils/metabolism*
  • Pedigree
  • Transcription Factors/genetics*
  • Zebrafish
PubMed: 28369036 Full text @ Nat. Genet.
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.