PRMT4 Is a Novel Coactivator of c-Myb-Dependent Transcription in Haematopoietic Cell Lines

Gundula Streubel,Uta-Maria Bauer,Rolf Müller,Sophia Teichmann,Hannah Berberich,Marc S Zeller,Karl-Heinz Klempnauer,Caroline Bouchard,Jürgen Adamkiewicz,Joseph Lipsick

doi:10.1371/journal.pgen.1003343

Abstract

Protein arginine methyltransferase 4 (PRMT4)–dependent methylation of arginine residues in histones and other chromatin-associated proteins plays an important role in the regulation of gene expression. However, the exact mechanism of how PRMT4 activates transcription remains elusive. Here, we identify the chromatin remodeller Mi2α as a novel interaction partner of PRMT4. PRMT4 binds Mi2α and its close relative Mi2β, but not the other components of the repressive Mi2-containing NuRD complex. In the search for the biological role of this interaction, we find that PRMT4 and Mi2α/β interact with the transcription factor c-Myb and cooperatively coactivate c-Myb target gene expression in haematopoietic cell lines. This coactivation requires the methyltransferase and ATPase activity of PRMT4 and Mi2, respectively. Chromatin immunoprecipitation analysis shows that c-Myb target genes are direct transcriptional targets of PRMT4 and Mi2. Knockdown of PRMT4 or Mi2α/β in haematopoietic cells of the erythroid lineage results in diminished transcriptional induction of c-Myb target genes, attenuated cell growth and survival, and deregulated differentiation resembling the effects caused by c-Myb depletion. These findings reveal an important and so far unknown connection between PRMT4 and the chromatin remodeller Mi2 in c-Myb signalling.

Highlights

Protein arginine methyltransferases (PRMTs) constitute a family of nine members (PRMT1-9) in mammals, which are characterised by a conserved catalytic domain [1,2]
Our manuscript deals with the Protein arginine methyltransferase 4 (PRMT4), which modifies arginine residues in histones and other chromatin-associated proteins and plays an important role in the regulation of gene expression
We addressed the question of how the transcriptional function of PRMT4 might contribute to cell lineage specification despite its ubiquitious expression pattern and how this could explain its involvement in tumorigenesis

Summary

Introduction

Protein arginine methyltransferases (PRMTs) constitute a family of nine members (PRMT1-9) in mammals, which are characterised by a conserved catalytic domain [1,2]. PRMTs regulate a plethora of cellular functions, including signal transduction, ribosome biogenesis, RNA processing, nucleocytoplasmic transport and chromatin-dependent processes, such as DNA repair, imprinting and transcriptional regulation, for which they usually require their catalytic activity. In agreement with their chromatin-related functions, a subgroup of PRMTs methylates histones as well as other chromatin-associated proteins and in this way contributes either to activation or repression of gene expression [4]. These various histone modifications at promoter-proximal nucleosomes of the target genes coincide with transcriptional activation

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