Gfi1b regulates the level of Wnt/β-catenin signaling in hematopoietic stem cells and megakaryocytes

Peiman Shooshtarizadeh, Anne Helness, Charles Vadnais, Nelleke Brouwer, Hugues Beauchemin, Riyan Chen, Halil Bagci, Frank J. T. Staal, Jean-François Coté and Tarik Möröy ()
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Peiman Shooshtarizadeh: Institut de recherches cliniques de Montréal
Anne Helness: Institut de recherches cliniques de Montréal
Charles Vadnais: Institut de recherches cliniques de Montréal
Nelleke Brouwer: Institut de recherches cliniques de Montréal
Hugues Beauchemin: Institut de recherches cliniques de Montréal
Riyan Chen: Institut de recherches cliniques de Montréal
Halil Bagci: Institut de recherches cliniques de Montréal
Frank J. T. Staal: Leiden University Medical Center
Jean-François Coté: Institut de recherches cliniques de Montréal
Tarik Möröy: Institut de recherches cliniques de Montréal

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract Gfi1b is a transcriptional repressor expressed in hematopoietic stem cells (HSCs) and megakaryocytes (MKs). Gfi1b deficiency leads to expansion of both cell types and abrogates the ability of MKs to respond to integrin. Here we show that Gfi1b forms complexes with β-catenin, its co-factors Pontin52, CHD8, TLE3 and CtBP1 and regulates Wnt/β-catenin-dependent gene expression. In reporter assays, Gfi1b can activate TCF-dependent transcription and Wnt3a treatment enhances this activation. This requires interaction between Gfi1b and LSD1 and suggests that a tripartite β-catenin/Gfi1b/LSD1 complex exists, which regulates Wnt/β-catenin target genes. Consistently, numerous canonical Wnt/β-catenin target genes, co-occupied by Gfi1b, β-catenin and LSD1, have their expression deregulated in Gfi1b-deficient cells. When Gfi1b-deficient cells are treated with Wnt3a, their normal cellularity is restored and Gfi1b-deficient MKs regained their ability to spread on integrin substrates. This indicates that Gfi1b controls both the cellularity and functional integrity of HSCs and MKs by regulating Wnt/β-catenin signaling pathway.

Date: 2019
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DOI: 10.1038/s41467-019-09273-z

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