Coactivator-associated arginine methyltransferase 1 (CARM1) is a positive regulator of the Cyclin E1 gene

Abstract

The Cyclin E1 gene (CCNE1) is an ideal model to explore the mechanisms that control the transcription of cell cycle-regulated genes whose expression rises transiently before entry into S phase. E2F-dependent regulation of the CCNE1 promoter was shown to correlate with changes in the level of H3-K9 acetylation͞methyl-ation of nucleosomal histones positioned at the transcriptional start site region. Here we show that, upon growth stimulation, the same region is subject to variations of H3-R17 and H3-R26 methylation that correlate with the recruitment of coactivator-associated arginine methyltransferase 1 (CARM1) onto the CCNE1 and DHFR promoters. Accordingly, CARM1-deficient cells lack these modifications and present lowered levels and altered kinetics of CCNE1 and DHFR mRNA expression. Consistently, reporter gene assays demonstrate that CARM1 functions as a transcriptional coactivator for their E2F1͞DP1-stimulated expression. CARM1 recruitment at the CCNE1 gene requires activator E2Fs and ACTR, a member of the p160 coactivator family that is frequently overexpressed in human breast cancer. Finally, we show that grade-3 breast tumors present coelevated mRNA levels of ACTR and CARM1, along with their transcriptional target CCNE1. All together, our results indicate that CARM1 is an important regulator of the CCNE1 gene.ACTR ͉ CCNE1 ͉ histone ͉ arginine methylation ͉ breast tumor C yclin E1 (CCNE1) protein and mRNA levels are tightly regulated as an endpoint of several regulatory pathways that are critical for growth control and frequently altered in cancer cells (1, 2). CCNE1 gene transcription is undetectable in G 0 and G 1 phases of the cell cycle, whereas it rises sharply during a narrow window of time that precedes each entry into S phase. Several pieces of evidence suggest that the periodic association of activators E2Fs-and E2F-pocket protein complexes regulate CCNE1 gene expression (3-18). E2F complexes bound to this gene were found to recruit chromatin modifiers, including members of the SNF2-like helicase family, type I histone deacetylases, the acetyltransferase CBP͞p300, the lysine methyl transferase SUVAR39H1, and the protein arginine N-methyltransferase (PRMT) 5 (7, 9-14, 17, 18), suggesting that they foster periodic chromatin remodeling of the CCNE1 promoter region (11,12,14). Notably, repression of the CCNE1 gene in G 0 -G 1 correlates with the methylation of H3-K9 and H4-R3 on a single nucleosome positioned at the transcriptional start site (11)(12)(13)(14). Conversely, the late G 1 activation of the CCNE1 gene correlates with decreased H3-K9 methylation and with enhanced H3͞H4 acetylation of the same chromatin region (11)(12)(13)(14). Here, we reveal that this CCNE1 proximal promoter region is targeted by another histone arginine methyl-transferase, the type I enzyme PRMT4 [coactivator-associated arginine methyltransferase (CARM1)] (19-25). PRMT4͞CARM1 was initially described as a transcriptional coactivator of the p160 family of nuclear receptor-associated factors (Src-1͞NCoA1, GRIP1͞TIF2͞Src-2͞ NC...

Interplay between chromatin remodelers and protein arginine methyltransferases

“…Similarly, PRMT1, PRMT4, and PRMT5 are all involved in transcriptional regulation of CYCLIN E1. During G 0 , PRMT5 is recruited to the CYCLIN E1 promoter to inhibit its transcription; however, when cells are induced to progress from G 1 to S CYCLIN E1 mRNA expression is induced due to the recruitment of PRMT1 and PRMT4 to the CYCLIN E1 promoter (El Messaoudi et al, 2006). Another example that illustrates the interplay between different members of the PRMT family comes from studies, which show that regulation of DNA repair is modulated by both PRMT1 and PRMT6.…”

Identification of a Novel Inhibitor of Coactivator-associated Arginine Methyltransferase 1 (CARM1)-mediated Methylation of Histone H3 Arg-17

“…CARM1 and PRMT1 interactions have also been shown to regulate gene expression in different contexts (11,12). CARM1 is a positive regulator of both cyclin E1 (13) and NF-B promoter activity (14). CARM1 also participates in various other cellular processes through its ability to methylate nonhistone substrates.…”

PRMT4 is involved in insulin secretion via the methylation of histone H3 in pancreatic β cells

“…Two groups have reported that asymmetric dimethylation of Arg2 in histone H3 was mainly catalyzed by PRMT6 (Guccione et al 2007, Iberg et al 2008. Chromatin immunoprecipitation (ChIP) analysis revealed elevated arginine dimethylation of histone H3R17 at the promoters for pS2 , E2F transcription factor 1 (Frietze et al 2008), and cyclin E1 (CCNE1; El Messaoudi et al 2006). The results of these studies indicate that PRMT4 plays a critical role in transcriptional regulation as a co-activator.…”