Maintaining adult hematopoiesis

An inability to properly sustain blood cell production results in the development of hematopoietic disorders. Epigenetic regulators have been shown to be involved in the function of hematopoietic stem and progenitor cells; however, dysfunction of these enzymes is associated with development of malignancies. In this episode Stephen Nimer and colleagues identify the type II arginine methyltransferase PRMT5 as an important regulator of adult hematopoiesis. Mice lacking PRMT5 developed fatal pancytopenia due to reduced proliferation of hematopoietic progenitor cells as the results of impaired cytokine signaling and increased p53 signaling. Hematopoietic stem cell populations were not initially reduced in these animals; however, this population was unable to restore blood cell populations in lethally irradiated mice. Together, the results of this study provide important insight into the role of PRMT5-mediated gene expression in maintaining hematopoietic homeostasis.

Published August 10, 2015, by The JCI

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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

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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