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 4

PRMT5 deletion leads to loss of functional HSPCs.

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PRMT5 deletion leads to loss of functional HSPCs. (A) BM cells isolated ...
(A) BM cells isolated from day-7 Prmt5fl/fl and Prmt5Δ/Δ mice were plated in methylcellulose cultures, supplemented with cytokines. Colonies were scored 7 days after plating (n = 3). (B) Left: LTC-IC assays using day-7 BM cells isolated from Prmt5fl/fl and Prmt5Δ/Δ mice. Cells were cocultured with MS5 cells for 4 weeks and then collected and plated in methylcellulose medium. Colonies were counted 1 week after plating. The number of cells plated in MS5 coculture is indicated in the graph. Right: CAFC assays using day-7 BM cells isolated from Prmt5fl/fl and Prmt5Δ/Δ mice. BM cells were cocultured with MS5 stromal cells for 5 weeks, and the number of cobblestone areas at the end of week 5 is plotted (n = 3). (C) Approximately 5 × 106 BM cells isolated from Prmt5fl/fl or Prmt5Δ/Δ mice 5 days after Cre induction were injected into lethally irradiated recipient CD45.1 mice. Survival of the mice was monitored daily (n = 8).