Mtf2-PRC2 control of canonical Wnt signaling is required for definitive erythropoiesis. [ChIP-seq]

genomic loci or increase enzymatic activity, while PRC2 core proteins are required for complex stability and global levels of trimethylation of histone 3 at lysine 27 (H3K27me3). Here, we demonstrate a role for the classical PRC2 accessory protein Mtf2/Pcl2 in the hematopoietic system that is more akin to that of a core PRC2 protein. Mtf2-/- erythroid progenitors demonstrate markedly decreased core PRC2 protein levels and a global loss of H3K27me3 at promoter-proximal regions. The resulting de-repression of transcriptional and signaling networks blocks definitive erythroid development, culminating in Mtf2-/- embryos dying by e15.5 due to severe anemia. Gene regulatory network (GRN) analysis demonstrated Mtf2 directly regulates Wnt signaling in erythroblasts, leading to activated canonical Wnt signaling in Mtf2-deficient erythroblasts, while chemical inhibition of canonical Wnt signaling rescued Mtf2-deficient erythroblast differentiation in vitro. Using a combination of in vitro, in vivo and systems analyses, we demonstrate that Mtf2 is a critical epigenetic regulator of Wnt signaling during erythropoiesis and recast the role of polycomb accessory proteins in a tissue-specific context. Overall design: ChIP-Seq based binding measurements of H3K4me3, PCL2 and IgG controls for mouse embryonic fetal liver cells; for PCL2 wt and knockout sorted for Ter119 presence/absence CD71+Ter119-/lo and CD71+Ter119high cell fractions from fetal livers of e14.5 WT and Pcl2-/- embryos were FACS-sorted and crosslinked by formaldehyde. ChIP-Seq was performed for H3K27me3 (and IgG control) in both cell fractions from both genotypes. Pcl2 ChIP-seq and its IgG control was performed on both cell fractions from wild-type embryos.