A gain-of-function mouse model identifies PRMT6 as a NF-κB coactivator

Abstract

Protein arginine methyltransferase 6 (PRMT6) is a nuclear enzyme that modifies histone tails. To help elucidate the biological function of PRMT6 in vivo, we generated transgenic mice that ubiquitously express PRMT6 fused to the hormone-binding portion of the estrogen receptor (ER*). The ER*-PRMT6 fusion is unstable and cytoplasmic, but upon systemic treatment with tamoxifen, it becomes stabilized and translocates into the nucleus. As a result, a dramatic increase in the H3R2me2a histone mark is observed. We found that one consequence of induced ER*-PRMT6 activation is increased IL-6 levels. IL-6 expression is regulated by the nuclear factor-kappa B (NF-κB) transcription factor, and PRMT6 functions as a coactivator of this pathway. We show that PRMT6 directly interacts with RelA, and that its overexpression enhances the transcriptional activity of an ectopic NF-κB reporter and endogenously regulates NF-κB target genes. PRMT6 is recruited, by RelA, to selective NF-κB target promoters upon TNF-α stimulation. Moreover, ER*-PRMT6 activation causes RelA accumulation in the nucleus. In summary, we observe that PRMT6 is recruited to chromatin at selective NF-κB target promoters, where it likely impacts the histone code and/or methylates other chromatin-associated proteins to facilitate transcription.

Protein Arginine Methyltransferase 6 (Prmt6) Is Essential for Early Zebrafish Development through the Direct Suppression of gadd45αa Stress Sensor Gene

“…These functions agree with the nuclear localization of Prmt6 (25). To date, many target genes of Prmt6 have been reported, including HoxA2 (17), thrombospondin-1 (26), p21 (20), p27 (27), p53 (21), Oct4 and Nanog (28), CD41 (29), and IL-6 (24).…”

“…Therefore, H3R2me2a mutually antagonizes H3K4me3 (17) and is known as a transcription-repressive mark. Prmt6 has been reported to regulate numerous biological process, including transcription (18 -21), DNA repair (22), DNA replication (23), and signal transduction (24). These functions agree with the nuclear localization of Prmt6 (25).…”

Histone arginine methylation in cocaine action in the nucleus accumbens

“…Prmt2, Prmt5, Prmt6, Prmt8, and Prmt9 (20, 21) were down-regulated by repeated cocaine administration, but not by a single cocaine exposure. Prmt8 is enriched in brain (22), and Prmt6 is the only type I PRMT exclusively located in the nucleus that modifies histone H3 (16,17,23).…”

Asymmetric arginine dimethylation of RelA provides a repressive mark to modulate TNFα/NF-κB response

“…Given that type I PRMTs are known to control NF-κB target genes (18)(19)(20)(21)(22), we investigated whether Rel proteins are modified by asymmetric arginine dimethylation. We tested PRMT1, PRMT4, and PRMT6, all of which are present in the nucleus and modify histones, for their ability to methylate the RelA subunit of NF-κB.…”

“…In addition to PRMT5, several type I PRMTs, including PRMT1, PRMT2, PRMT4, and PRMT6, have been shown to coregulate NF-κB target genes (18)(19)(20)(21)(22); however, it remains unclear whether Rel proteins are also modified by type I PRMTs that methylate arginines asymmetrically, thereby leading to the formation of asymmetric ω-N G ,N G -dimethylarginine (ADMA).…”