title: 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.
authors.affiliation: The University of Texas MD Anderson Cancer Center, Science Park, P.O. Box 389, Smithville, TX 78957, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Di Lorenzo
authors.affiliation: The University of Texas MD Anderson Cancer Center, Science Park, P.O. Box 389, Smithville, TX 78957, USA.
authors.forename: Yanzhong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: The University of Texas MD Anderson Cancer Center, Science Park, P.O. Box 389, Smithville, TX 78957, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Macaluso
authors.affiliation: The University of Texas MD Anderson Cancer Center, Science Park, P.O. Box 389, Smithville, TX 78957, USA mtbedford@mdanderson.org.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bedford
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D009687:Nuclear Proteins; D011960:Receptors, Estrogen; D051996:Transcription Factor RelA; D013629:Tamoxifen; C447833:PRMT6 protein, human; C577312:PRMT6 protein, mouse; D011484:Protein-Arginine N-Methyltransferases