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

• Published in: Nature communications Vol. 10; no. 1; p. 1270
• Main Authors: Shooshtarizadeh, Peiman, Helness, Anne, Vadnais, Charles, Brouwer, Nelleke, Beauchemin, Hugues, Chen, Riyan, Bagci, Halil, Staal, Frank J T, Coté, Jean-François, Möröy, Tarik
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 20.03.2019; Nature Publishing Group UK; Nature Portfolio
• Subjects: Alcohol Oxidoreductases - genetics; Alcohol Oxidoreductases - metabolism; Animals; beta Catenin - genetics; beta Catenin - metabolism; Co-Repressor Proteins - genetics; Co-Repressor Proteins - metabolism; Deregulation; DNA Helicases - genetics; DNA Helicases - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene expression; Gene Expression Regulation; Gene Ontology; Genes; Genes, Reporter; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; HEK293 Cells; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Histone Demethylases - genetics; Histone Demethylases - metabolism; Humans; K562 Cells; Megakaryocytes; Megakaryocytes - cytology; Megakaryocytes - metabolism; Mice; Mice, Knockout; Molecular Sequence Annotation; Primary Cell Culture; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - genetics; Repressor Proteins - deficiency; Repressor Proteins - genetics; Signal transduction; Signaling; Stem cells; Substrates; Tamoxifen; Transcription; Wnt protein; Wnt Signaling Pathway; Wnt3A Protein - genetics; Wnt3A Protein - metabolism; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09273-z

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.