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

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 beta-catenin, its co-factors Pontin52, CHD8, TLE3 and CtBP1 and regulates Wnt/beta-catenindependent 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 beta-catenin/Gfi1b/LSD1 complex exists, which regulates Wnt/beta-catenin target genes. Consistently, numerous canonical Wnt/beta-catenin target genes, co-occupied by Gfi1b, beta-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/beta-catenin signaling pathway.