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SMARCD2 subunit of SWI/SNF chromatin-remodeling complexes mediates granulopoiesis through a CEBPɛ dependent mechanism

Nature Genetics volume 49, pages 753764 (2017) | Download Citation

Abstract

Recent studies suggest that individual subunits of chromatin-remodeling complexes produce biologically specific meaning in different cell types through combinatorial assembly. Here we show that granulocyte development requires SMARCD2, a subunit of ATP-dependent SWI/SNF (BAF) chromatin-remodeling complexes. Smarcd2-deficient mice fail to generate functionally mature neutrophils and eosinophils, a phenotype reminiscent of neutrophil-specific granule deficiency (SGD) in humans, for which loss-of-function mutations in CEBPE (encoding CEBPɛ) have been reported. SMARCD2-containing SWI/SNF complexes are necessary for CEBPɛ transcription factor recruitment to the promoter of neutrophilic secondary granule genes and for granulocyte differentiation. The homologous SMARCD1 protein (63% identical at the amino acid level) cannot replace the role of SMARCD2 in granulocyte development. We find that SMARCD2 functional specificity is conferred by its divergent coiled-coil 1 and SWIB domains. Strikingly, both CEBPE and SMARCD2 loss-of-function mutations identified in patients with SGD abolish the interaction with SWI/SNF and thereby secondary granule gene expression, thus providing a molecular basis for this disease.

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Acknowledgements

The authors thank B. Turgeon, S. Harton and V. Paradis for generating the Smarcd2-deficient mice; J. Gervais for veterinary services, C. Klein (Ludwig Maximilians University) for the SMARCD2 SGD mutants and critical discussions, J. Féthière for the antibodies to SMARCD1, SMARCD2 and SMARCD3, G.R. Crabtree (Stanford University) for J1 antibody; J. Krosl and T. Hoang for hemopoietic cytokines; P. Gendron and V. Lavallée for bioinformatics analyses; D. Gagné and G. Dulude for flow cytometry; C. Charbonneau for microscopy; J. Hébert and the Quebec Leukemia Cell Bank (BCLQ) for human samples; and J. Chagraoui for scientific discussions. P.P. is supported by a scholarship from the Cole Foundation. These studies were also supported in part by grants from the Canadian Institutes for Health Research (MOP_133546 to J.L.) and a Canada Research Chair Tier 2 to J.A.L.

Author information

Affiliations

  1. Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada.

    • Pierre Priam
    • , Veneta Krasteva
    • , Philippe Rousseau
    • , Louis Gaboury
    • , Guy Sauvageau
    •  & Julie A Lessard
  2. Department of Pathology and Cellular Biology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.

    • Pierre Priam
    • , Veneta Krasteva
    • , Louis Gaboury
    •  & Julie A Lessard
  3. Division of Hematology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.

    • Giovanni D'Angelo
    •  & Guy Sauvageau
  4. Leukemia Cell Bank of Quebec, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.

    • Guy Sauvageau
  5. Department of Medicine, University of Montreal, Montreal, Quebec, Canada.

    • Guy Sauvageau

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Contributions

J.A.L. contributed to study design and supervision. P.P., V.K., P.R., G.D., G.S. and L.G. contributed to data acquisition and analysis. P.P. and J.L. contributed to writing and revision of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Julie A Lessard.

Integrated supplementary information

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–14

Excel files

  1. 1.

    Supplementary Table 1

    List of antibodies used in these studies.

  2. 2.

    Supplementary Table 2

    TPM values of RNA–seq data sets of BAF60b-knockout and control granulocyte–macrophage progenitors (n = 3 independent experiments).

  3. 3.

    Supplementary Table 3

    Prediction of CEBPɛ-binding sites in the promoter of neutrophilic granule genes expressed at a mean TPM value above 0.3 in control granulocyte–macrophage progenitors (n = 3 independent experiments).

  4. 4.

    Supplementary Table 4

    List of oligonucleotides used in these studies.

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DOI

https://doi.org/10.1038/ng.3812

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