Arginine methyltransferase PRMT5 is essential for sustaining normal adult hematopoiesis
Fan Liu, … , Luisa Luciani, Stephen D. Nimer
Fan Liu, … , Luisa Luciani, Stephen D. Nimer
Published August 10, 2015
Citation Information: J Clin Invest. 2015;125(9):3532-3544. https://doi.org/10.1172/JCI81749.
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Research Article Hematology

Arginine methyltransferase PRMT5 is essential for sustaining normal adult hematopoiesis

Abstract

Epigenetic regulators play critical roles in normal hematopoiesis, and the activity of these enzymes is frequently altered in hematopoietic cancers. The major type II protein arginine methyltransferase PRMT5 catalyzes the formation of symmetric dimethyl arginine and has been implicated in various cellular processes, including pluripotency and tumorigenesis. Here, we generated Prmt5 conditional KO mice to evaluate the contribution of PRMT5 to adult hematopoiesis. Loss of PRMT5 triggered an initial but transient expansion of hematopoietic stem cells (HSCs); however, Prmt5 deletion resulted in a concurrent loss of hematopoietic progenitor cells (HPCs), leading to fatal BM aplasia. PRMT5-specific effects on hematopoiesis were cell intrinsic and depended on PRMT5 methyltransferase activity. We found that PRMT5-deficient hematopoietic stem and progenitor cells exhibited severely impaired cytokine signaling as well as upregulation of p53 and expression of its downstream targets. Together, our results demonstrate that PRMT5 plays distinct roles in the behavior of HSCs compared with HPCs and is essential for the maintenance of adult hematopoietic cells.

Authors

Fan Liu, Guoyan Cheng, Pierre-Jacques Hamard, Sarah Greenblatt, Lan Wang, Na Man, Fabiana Perna, Haiming Xu, Madhavi Tadi, Luisa Luciani, Stephen D. Nimer

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Figure 8

PRMT5 loss impairs the cell surface expression of cytokine receptors.

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PRMT5 loss impairs the cell surface expression of cytokine receptors. (A...
(A) BM cells were isolated from day-7 control and Prmt5-KO mice and stained for HSPC markers and several cytokine receptors. Percentages of FLT3-, IL-6Rα–, and IL-3Rα–positive cells in LK and LSK cell populations were plotted. (B and C) Day-7 control and Prmt5-KO BM cells were stained for HSPC cell surface marker expression and subjected to FACS analysis. Representative histogram shows decreased c-Kit expression in day-7 PRMT5-null HSPCs (B). The MFI of c-Kit staining in control and PRMT5-null LK and LSK cells was plotted as the mean ± SD (n = 5) (C). P values were determined by a 2-tailed Student’s t test.