Journal Article

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

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

2017

Overview

Christoph Klein and colleagues identify loss-of-function mutations in SMARCD2 ( BAF60b ) that lead to neutropenia, specific granule deficiency and myelodysplasia. They show that SMARCD2 controls differentiation of myeloid–erythroid progenitor cells through interaction with CEBPɛ and that reduced SMARCD2 levels cause transcription and chromatin alterations in acute myeloid leukemia cells. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/1 / 13/31 / 38/23 / 38/91 / 45/22 / 631/208/200 / 631/67/1990/1673 / 64/116 / 64/60 / 692/308/575 / 692/699/249/1570 / 96/100 / 96/21 / Aberration / Agriculture / Animal Genetics and Genomics / Animals / Animals, Genetically Modified / Base Sequence / Bioinformatics / Biomedicine / Blast cells / Cancer Research / Cell Differentiation - genetics / Cell Line, Tumor / Cells (biology) / Chromatin / Chromatin Assembly and Disassembly / Chromosomal Proteins, Non-Histone / Colleges & universities / Differentiation / DNA Mutational Analysis / Family Health / Female / Gene Function / Gene Regulatory Networks / Genes / Genomes / Granular materials / Granulocytes / Hospitals / Human Genetics / Humans / In vitro methods and tests / Leukemia / Leukemia, Promyelocytic, Acute - genetics / Leukemia, Promyelocytic, Acute - pathology / Male / Medical screening / Mice / Mice, Inbred C57BL / Mice, Knockout / Mutation / Neutropenia / Neutrophils / Neutrophils - metabolism / Patients / Pediatrics / Pedigree / Proteins / Software / Transcription factors / Transcription Factors - genetics / Tumor suppressor genes / Zebrafish