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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

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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 1

Deletion of PRMT5 in adult BM results in severe pancytopenia.

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Deletion of PRMT5 in adult BM results in severe pancytopenia.
(A) Prmt5 ...
(A) Prmt5 mRNA levels decreased when mouse BM cells underwent terminal myeloid and erythroid differentiation. WT BM HSCs and their differentiated progeny were flow sorted on the basis of their cell surface marker expression, and Prmt5 mRNA levels were determined by qPCR (normalized to Hprt1 expression). A representative PCR result from 3 independent experiments (cells in each experiment were pulled together from 3 mice) is shown. MPPs, multipotent progenitors; CMPs, common myeloid progenitors; GMPs, granulocyte-macrophage progenitors. (B) PRMT5 protein levels were determined by Western blot analysis using sorted populations of WT BM cells. Numbers indicate the densitometry of the PRMT5 bands normalized to β-actin. (C) The cellular level of symmetrically dimethylated arginine was detected using an antibody against the Symmetric Di-Methyl Arginine Motif (catalog 13222; Cell Signaling Technology). This antibody recognizes 2 major bands of approximately 25 kDa and 15 kDa. (D) Loss of PRMT5 led to pancytopenia within 15 days. Complete blood count (CBC) analysis of peripheral blood wbc, rbc, and platelet (PLT) counts at 0, 7, and 15 days after injection (d.p.i.) are shown (n = 5). (E) BM cellularity was determined 7 and 15 d.p.i. in Prmt5fl/fl and Prmt5Δ/Δ mice (n = 5). (F) The cellularity of the thymus obtained from Prmt5fl/fl and Prmt5Δ/Δ mice was determined 15 d.p.i. (n = 5). (G) Representative images show H&E-stained cross sections of femurs isolated from the control and Prmt5Δ/Δ mice. Original magnification, ×200. (H) Representative image shows reduced size of the thymus from a Prmt5Δ/Δ mouse compared with that from a Prmt5fl/fl mouse on day 15. All P values were determined by a 2-tailed Student’s t test.
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