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

Abstract

Hematopoietic differentiation is driven by transcription factors, which orchestrate a finely 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 is the association of the transcription factor RUNX1 with 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 inhibitors leads to upregulation of erythroid genes and promotes erythropoiesis. Our data reveal that PRMT6 plays a role in the control of erythroid/megakaryocytic differentiation and open up the possibility that manipulation of PRMT6 activity could facilitate enhanced erythropoiesis for therapeutic use.

PRMT6 activates cyclin D1 expression in conjunction with the transcription factor LEF1

“…However, little is known about the influence of PRMT6 on proliferation in hematopoiesis. We found that PRMT6 inhibits erythropoiesis and recent data supports the idea that PRMT6 plays a role in cell growth 25 . To further investigate this notion, we determined expression of PRMT6 in distinct hematopoietic cell lines.…”

“…Furthermore, PRMT6 influences embryonic stem cell identity 24 . In the hematopoietic system the transcription factor RUNX1 recruits PRMT6, which contributes to the repression of RUNX1 erythroid target genes 25 – 27 . PRMT6 expression is associated with several cancer types 15 , 28 – 30 and pharmacological inhibitors are under investigation as therapeutic inhibitors 31 , 32 .…”

Stress erythropoiesis in atherogenic mice

“…First, we determined by RT-qPCR the expression of genes that could confirm a correct separation of both types of cells. Single cell profiling has revealed higher mRNA expression of the erythroid markers Ankyrin1 and Glycophorin A in erythroid-biased CD71 + CD41 − MEPs opposed to non-biased CD71 − CD41 − MEPs 6 – 8 . Accordingly, splenic CD71 + CD41 − MEPs from both control and atherogenic mice showed higher mRNA expression of these erythroid markers than CD71 − CD41 − MEPs (see Supplemental Figure S10 A online).…”

K562 erythroleukemia line as a possible reticulocyte source to culture Plasmodium vivax and its surrogates

“…Protein arginine methyltransferase 6 (PRMT6), whose role as an inhibitor of genes necessary to erythropoiesis has only recently been revealed, is another important regulator. In this context, it has been found that the PRMT6 inhibitor MS023 promotes erythroid differentiation in K562 [47]. From this small selection of important regulatory factors, it can be shown that for many parameters of erythropoiesis, an even deeper understanding must be gained to fully elucidate the regulatory processes of erythroid differentiation.…”