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 2

PRMT5 loss impairs erythroid differentiation and T cell development.

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PRMT5 loss impairs erythroid differentiation and T cell development. (A)...
(A) The stage of erythroid differentiation in BM and spleen from Prmt5fl/fl and Prmt5Δ/Δ mice was determined by Ter119/CD71 double staining and FACS analysis at 7 d.p.i. Note that the cells were stained without rbc lysis. Results are representative of 3 experiments, with 2 to 3 mice per group in each experiment. B) Lin–, c-Kit+, and Sca1– progenitor cells isolated from day-7 mouse BM were further stained for CD34 and FcRII/III to distinguish the CMP (CD34+/FcRII/III–), GMP (CD34+/FcRII/III+), and MEP (CD34–/FcRII/III–) cell populations. The percentage of each population is indicated in the plots. Results are representative of 3 experiments, with 2 to 3 mice per group in each experiment. (C) Thymocytes were stained for the CD4, CD8, CD25, and CD44 cell surface markers. The distribution of CD25/CD44 subsets within the CD4/CD8 DN cell population is shown for Prmt5fl/fl , Prmt5+/Δ, and Prmt5Δ/Δ mice. (D) The frequencies of each DN subset (DN1–DN4) on days 9 and 15 are plotted for the Prmt5fl/fl and Prmt5Δ/Δ mice (n = 3). P values were determined by a 2-tailed Student’s t test.