Abstract
The establishment of cell type specific gene expression by transcription factors and their epigenetic cofactors is central for cell fate decisions. Protein arginine methyltransferase 6 (PRMT6) is an epigenetic regulator of gene expression mainly through methylating arginines at histone H3. This way it influences cellular differentiation and proliferation. PRMT6 lacks DNA-binding capability but is recruited by transcription factors to regulate gene expression. However, currently only a limited number of transcription factors have been identified, which facilitate recruitment of PRMT6 to key cell cycle related target genes. Here, we show that LEF1 contributes to the recruitment of PRMT6 to the central cell cycle regulator CCND1 (Cyclin D1). We identified LEF1 as an interaction partner of PRMT6. Knockdown of LEF1 or PRMT6 reduces CCND1 expression. This is in line with our observation that knockdown of PRMT6 increases the number of cells in G1 phase of the cell cycle and decreases proliferation. These results improve the understanding of PRMT6 activity in cell cycle regulation. We expect that these insights will foster the rational development and usage of specific PRMT6 inhibitors for cancer therapy.
Highlights
Methylation of arginine residues in histone and nonhistone proteins is catalyzed by protein arginine methyltransferases (PRMTs)[1], which constitute a family of conserved enzymes in mammals
We found that Protein arginine methyltransferase 6 (PRMT6) inhibits erythropoiesis and recent data supports the idea that PRMT6 plays a role in cell growth[25]
The expression of the shPRMT6 as well as the shcontrol was confirmed until the end of the experiment, as the GFP marker was detected until day 24 (Fig. 1D)
Summary
Methylation of arginine residues in histone and nonhistone proteins is catalyzed by protein arginine methyltransferases (PRMTs)[1], which constitute a family of conserved enzymes in mammals. Our data show that LEF1 and PRMT6 cooperate in regulation of the cell cycle gene CCND1 (Cyclin D1). Identification of PRMT6 interaction partners the detailed mechanism of PRMT6 activity on proliferation in cancer is not yet identified, the recruitment of PRMT6 by transcription factors to target genes involved in cell-cycle regulation is part of this process. Identification of CCND1 as a cell cycle relevant PRMT6/ LEF1 target gene
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