1. Chromatin-remodeling factor SMARCD2 regulates transcriptional networks controlling differentiation of neutrophil granulocytes
- Author
-
Christoph Ziegenhain, Jacek Puchałka, Daniel Petersheim, Heinrich Schmidt, Miguel R. Abboud, Marlon R. Schneider, Vahid Pazhakh, Maik Dahlhoff, Peter D. Arkwright, Eckhard Wolf, Christoph Klein, Alejandro A. Schäffer, Wolfgang Enard, Julien Gagneur, Ehsan Bahrami, Hans-Peter Horny, Tomas Racek, Yanxin Fan, Graham J. Lieschke, Maximilian Witzel, Meino Rohlfs, Asbjørg Stray-Pedersen, Peter Krawitz, and Christian Mertes more...
- Subjects
0301 basic medicine ,Male ,Chromosomal Proteins, Non-Histone ,Neutrophils ,DNA Mutational Analysis ,Chromatin Remodeling Factor ,Biology ,leukemogenesis ,Article ,Animals, Genetically Modified ,03 medical and health sciences ,0302 clinical medicine ,Leukemia, Promyelocytic, Acute ,Transcription (biology) ,congenital neutropenia ,hemic and lymphatic diseases ,Cell Line, Tumor ,Genetics ,Animals ,Humans ,primary immunodeficiency disorder ,Gene Regulatory Networks ,Progenitor cell ,Congenital Neutropenia ,Zebrafish ,Regulation of gene expression ,specific granule deficiency ,Family Health ,Mice, Knockout ,Base Sequence ,Myeloid leukemia ,Cell Differentiation ,Chromatin Assembly and Disassembly ,Chromatin ,Cell biology ,Hematopoiesis ,Pedigree ,Mice, Inbred C57BL ,Haematopoiesis ,030104 developmental biology ,030220 oncology & carcinogenesis ,Immunology ,Female ,SWI/SNF complex ,Transcription Factors - 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. more...
- Published
- 2017
- Full Text
- View/download PDF