TY - JOUR
T1 - A gain-of-function mouse model identifies PRMT6 as a NF-κB coactivator
AU - Di Lorenzo, Alessandra
AU - Yang, Yanzhong
AU - Macaluso, Marc
AU - Bedford, Mark T.
N1 - Funding Information:
National Institutes of Health [NIH; DK062248 to M.T.B.]; Cancer Prevention and Research Institute of Texas (CPRIT) [RP110471]; Schissler Foundation Fellowship [to A.D.L.]; Julia Jones Matthews Cancer Research Scholar Foundation Award [to A.D.L.]. Funding for open access charge: NIH [DK062248 to M.T.B.]; CPRIT [RP110471]; Schissler Foundation Fellowship [to A.D.L.]; Julia Jones Matthews Cancer Research Scholar Foundation Award [to A.D.L.]. Conflict of interest statement. M.T.B. is a cofounder of EpiCypher.
PY - 2014/7/29
Y1 - 2014/7/29
N2 - 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.
AB - 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.
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U2 - 10.1093/nar/gku530
DO - 10.1093/nar/gku530
M3 - Article
C2 - 24939901
AN - SCOPUS:84905581017
SN - 0305-1048
VL - 42
SP - 8297
EP - 8309
JO - Nucleic acids research
JF - Nucleic acids research
IS - 13
ER -