Chromatin-remodeling factor SMARCD2 regulates transcriptional networks controlling differentiation of neutrophil granulocytes
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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. © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
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Animals, Animals, genetically modified, Base sequence, Cell differentiation, Cell line, tumor, Chromatin assembly and disassembly, Dna mutational analysis, Family health, Female, Gene regulatory networks, Humans, Leukemia, promyelocytic, acute, Male, Mice, inbred c57bl, Mice, knockout, Neutrophils, Pedigree, Transcription factors, Zebrafish, Alpha 1 antitrypsin, Cathelicidin, Colony stimulating factor 1, Cytokine receptor, Granulocyte colony stimulating factor, Granulocyte macrophage colony stimulating factor, Haptocorrin, Lactoferrin, Neutrophil collagenase, Swi/snf related matrix associated actin dependent regulator of chromatin subfamily b member 2, Transcription factor, Unclassified drug, Smarcd2 protein, human, Allele, Article, Bacterial infection, Cardiac muscle cell, Case report, Cell maturation, Cell surface, Chromosome 17, Chronic diarrhea, Comparative study, Controlled study, Erythroid precursor cell, Gene expression, Granulopoiesis, Homozygosity, Human, Human cell, In vitro study, Loss of function mutation, Major histocompatibility complex, Mouse, Myeloid progenitor cell, Neutropenia, Neutrophil, Nonhuman, Parasitosis, Priority journal, Protein protein interaction, Sanger sequencing, Translation initiation, Whole exome sequencing, Zebra fish, Animal, C57bl mouse, Gene regulatory network, Genetics, Knockout mouse, Metabolism, Nucleotide sequence, Pathology, Promyelocytic leukemia, Transgenic animal, Tumor cell line