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Published 20 January 2004. doi:10.1083/jcb.200307056
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 164, Number 2, 175-184
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Article

 FoxO3a regulates erythroid differentiation and induces BTG1, an activator of protein arginine methyl transferase 1

Walbert J. Bakker1, Montserrat Blázquez-Domingo1, Andrea Kolbus2, Janey Besooyen1, Peter Steinlein2, Hartmut Beug2, Paul J. Coffer3, Bob Löwenberg1, Marieke von Lindern1, and Thamar B. van Dijk1

1 Department of Hematology, Erasmus MC, 3015 GE Rotterdam, Netherlands
2 Research Institute of Molecular Pathology, A-1030 Vienna, Austria
3 Department of Pulmonary Disease, University Medical Center, 3584 CX Utrecht, Netherlands

Address correspondence to Marieke von Lindern, Dept. of Hematology, Erasmus MC, PO Box 1738, 3000 DR Rotterdam, Netherlands. Tel.: 31-10-408-7961. Fax: 31-10-408-9470. email: m.vonlindern{at}erasmusmc.nl

Erythropoiesis requires tight control of expansion, maturation, and survival of erythroid progenitors. Because activation of phosphatidylinositol-3-kinase (PI3K) is required for erythropoietin/stem cell factor–induced expansion of erythroid progenitors, we examined the role of the PI3K-controlled Forkhead box, class O (FoxO) subfamily of Forkhead transcription factors. FoxO3a expression and nuclear accumulation increased during erythroid differentiation, whereas untimely induction of FoxO3a activity accelerated differentiation of erythroid progenitors to erythrocytes. We identified B cell translocation gene 1 (BTG1)/antiproliferative protein 2 as a FoxO3a target gene in erythroid progenitors. Promoter studies indicated BTG1 as a direct target of FoxO3a. Expression of BTG1 in primary mouse bone marrow cells blocked the outgrowth of erythroid colonies, which required a domain of BTG1 that binds protein arginine methyl transferase 1. During erythroid differentiation, increased arginine methylation coincided with BTG1 expression. Concordantly, inhibition of methyl transferase activity blocked erythroid maturation without affecting expansion of progenitor cells. We propose FoxO3a-controlled expression of BTG1 and subsequent regulation of protein arginine methyl transferase activity as a novel mechanism controlling erythroid expansion and differentiation.

Key Words: erythropoiesis; Forkhead transcription factors; protein arginine methylation; cDNA microarray; PRMT1

The online version of this article contains supplemental material.

A. Kolbus's present address is Dept. of Gynecologic Endocrinology and Reproductive Medicine, University of Vienna Medical School, A-1090 Vienna, Austria.

T.B. van Dijk's present address is Dept. of Cell Biology and Genetics, Erasmus MC, 3015 GE Rotterdam, Netherlands.

Abbreviations used in this paper: 4OHT, 4-hydroxytamoxifen; BTG1, B cell translocation gene 1; DBE, Daf-16 binding element; Dex, dexamethasone; Epo, erythropoietin; ER, estrogen receptor; FoxO, Forkhead box, class O; GM-CSF, granulocyte–macrophage colony-stimulating factor; MTA, 5'-deoxy-5'-methylthioadenosine; PI3K, phosphatidylinositol-3-kinase; PRMT1, protein arginine methyl transferase 1; RNAi, RNA interference; SCF, stem cell factor.


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