PRMT4 Is a Novel Coactivator of c-Myb-Dependent Transcription in Haematopoietic Cell Lines
et al. (2013) PRMT4 Is a Novel Coactivator of c-Myb-Dependent Transcription in
Haematopoietic Cell Lines. PLoS Genet 9(3): e1003343. doi:10.1371/journal.pgen.1003343
PRMT4 Is a Novel Coactivator of c-Myb-Dependent Transcription in Haematopoietic Cell Lines
Gundula Streubel 0
Caroline Bouchard 0
Hannah Berberich 0
Marc S. Zeller 0
Sophia Teichmann 0
Ju rgen Adamkiewicz 0
Rolf Mu ller 0
Karl-Heinz Klempnauer 0
Uta-Maria Bauer 0
Joseph Lipsick, Stanford University School of Medicine, United States of America
0 1 Smurfit Institute of Genetics, Trinity College Dublin , Dublin, Ireland , 2 Institute for Molecular Biology and Tumor Research (IMT), University of Marburg , Marburg, Germany , 3 Centre de Regulacio Gen o`mica (CRG) and UPF , Barcelona , Spain , 4 Institute for Biochemistry, Westfa lische Wilhelms-University of Mu nster , M u nster , Germany
Protein arginine methyltransferase 4 (PRMT4)-dependent methylation of arginine residues in histones and other chromatinassociated 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 Mi2a as a novel interaction partner of PRMT4. PRMT4 binds Mi2a and its close relative Mi2b, but not the other components of the repressive Mi2containing NuRD complex. In the search for the biological role of this interaction, we find that PRMT4 and Mi2a/b 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 Mi2a/b 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.
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Funding: This work was funded as part of the FOR531, TRR81, TRR17, and Ba 2292/1 by the DFG (Deutsche Forschungsgemeinschaft), as part of LOEWE (Tumor
and Inflammation) by the Land Hessen and by the BMBF (Bundesministerium f ur Bildung und Forschung) to U-MB. The funders had no role in study design, data
collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
. These authors contributed equally to this work.
Protein arginine methyltransferases (PRMTs) constitute a family
of nine members (PRMT1-9) in mammals, which are
characterised by a conserved catalytic domain [1,2]. They
posttranslationally mono- and dimethylate arginine residues in
proteins using S-adenosylmethionine (SAM) as methyl group
donor. Dimethylation can be either asymmetric or symmetric [3].
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].
PRMT4, also named CARM1 (coactivator associated arginine
methyltransferase 1), was the first member linked to transcriptional
activation through asymmetric dimethylation of histone H3 at
arginine 17 (H3R17me2a) [57]. Together with other
coactivators, such as PRMT1 and the histone acetyltransferase (HAT)
CBP/p300, PRMT4 is recruited to specific target genes through
interaction with transcription factors, for example p53, NF-kB and
nuclear hormone receptors such as the estrogen receptor (ER) [8
11]. The hierarchy of sequential coactivator recruitment in ER
signalling has been studied in detail revealing that
PRMT1mediated dimethylation of histone H4 at arginine 3 (H4R3me2a)
occurs as an early event following hormone treatment and is a
prerequisite for promoter hyperacetylation [12,13]. Subsequent
histone acetylation by CBP/p300 facilitates promoter recognition
by PRMT4 and methylation of H3R17 [14]. These various
histone modifications at promoter-proximal nucleosomes of the
target genes coincide with transcriptional activation.
PRMT1- and CBP/p300-mediated histone modifications are
required for the subsequent recruitment and enhanced activity of
coactivators explaining their direct support of active transcription
[12,14,15]. Furthermore, histone acetylation is read by Bromo
domain-containing proteins, such as the TAFII250 subunit of the
TFIID complex, linking this mo (...truncated)