Protein arginine methyltransferase 6 controls erythroid gene expression and differentiation of human CD34+ progenitor cells

Hematopoietic differentiation is driven by transcription factors, which orchestrate a fine tuned transcriptional network. At bipotential branching points lineage decisions are made, where key transcription factors initiate cell type specific gene expression programs. These programs are stabilized by the epigenetic activity of recruited chromatin modifying cofactors. An example gives the association of the transcription factor RUNX1 with the protein arginine methyltransferase 6 (PRMT6) at the megakaryocytic/erythroid bifurcation. However, little is known about the specific influence of PRMT6 on this important branching point. Here, we show that PRMT6 inhibits erythroid gene expression during megakaryopoiesis of primary human CD34+ progenitor cells. PRMT6 is recruited to erythroid genes, such as glycophorin A. Consequently, a repressive histone modification pattern with high H3R2me2a and low H3K4me3 is established. Importantly, inhibition of PRMT6 by shRNA or small molecule inhibitor leads to an upregulation of erythroid genes and promotes erythropoiesis. Our data reveal a role of PRMT6 in the control of erythroid/megakaryocytic differentiation and open the possibility that manipulation of PRMT6 activity can facilitate enhanced erythropoiesis for therapeutic use.