Arginine methyltransferase CARM1 is a promoter-specific regulator of NF-kappaB-dependent gene expression.
Nuclear factor kappaB (NF-kappaB) plays an important role in the transcriptional regulation of genes involved in inflammation and cell survival. Here, we show that coactivator-associated arginine methyltransferase CARM1/PRMT4 is a novel transcriptional coactivator of NF-kappaB and functions as a promoter-specific regulator of NF-kappaB recruitment to chromatin. Carm1 knockout cells showed impaired expression of a subset of NF-kappaB-dependent genes upon TNFalpha or LPS stimulation. CARM1 forms a complex with p300 and NF-kappaB in vivo and interacts directly with the NF-kappaB subunit p65 in vitro. CARM1 seems to act in a gene-specific manner mainly by enhancing NF-kappaB recruitment to cognate sites. Moreover, CARM1 synergistically coactivates NF-kappaB-mediated transactivation, in concert with the transcriptional coactivators p300/CREB-binding protein and the p160 family of steroid receptor coactivators. For at least a subset of CARM1-dependent NF-kappaB target genes, the enzymatic activities of both CARM1 and p300 are necessary for the observed synergy between CARM1 and p300. Our results suggest that the cooperative action between protein arginine methyltransferases and protein lysine acetyltransferases regulates NF-kappaB-dependent gene activation in vivo.
Covic
Marcela
M
Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Zurich, Switzerland.
Hassa
Paul O
PO
Saccani
Simona
S
Buerki
Christine
C
Meier
Nadja I
NI
Lombardi
Cornelia
C
Imhof
Ralph
R
Bedford
Mark T
MT
Natoli
Gioacchino
G
Hottiger
Michael O
MO
D000818:Animals; D002460:Cell Line; D054357:Chemokine CXCL10; D054426:Chemokine CXCL2; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D050881:E1A-Associated p300 Protein; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism; D046911:Macromolecular Substances; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D051958:Nuclear Receptor Coactivator 2; D011401:Promoter Regions, Genetic; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D054357:Chemokine CXCL10; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; C404915:Cxcl2 protein, mouse; D006657:Histones; D008070:Lipopolysaccharides; D046911:Macromolecular Substances; C498001:NCOA2 protein, human; D016328:NF-kappa B; C498002:Ncoa2 protein, mouse; D009687:Nuclear Proteins; D051958:Nuclear Receptor Coactivator 2; D015534:Trans-Activators; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse