A transcriptional switch mediated by cofactor methylation.
We describe a molecular switch based on the controlled methylation of nucleosome and the transcriptional cofactors, the CREB-binding proteins (CBP)/p300. The CBP/p300 methylation site is localized to an arginine residue that is essential for stabilizing the structure of the KIX domain, which mediates CREB recruitment. Methylation of KIX by coactivator-associated arginine methyltransferase 1 (CARM1) blocks CREB activation by disabling the interaction between KIX and the kinase inducible domain (KID) of CREB. Thus, CARM1 functions as a corepressor in cyclic adenosine monophosphate signaling pathway via its methyltransferase activity while acting as a coactivator for nuclear hormones. These results provide strong in vivo and in vitro evidence that histone methylation plays a key role in hormone-induced gene activation and define cofactor methylation as a new regulatory mechanism in hormone signaling.
Xu
W
W
Gene Expression Laboratory, Department of Biological Chemistry, University of California Davis Cancer Center/Basic Science, Sacramento, CA 95817, USA.
Chen
H
H
Du
K
K
Asahara
H
H
Tini
M
M
Emerson
B M
BM
Montminy
M
M
Evans
R M
RM
D000123:Acetyltransferases / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019281:Dimerization; D050881:E1A-Associated p300 Protein; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D051548:Histone Acetyltransferases; D006657:Histones / Q000378:metabolism; D008745:Methylation; D008969:Molecular Sequence Data; D020932:Nerve Growth Factor / Q000494:pharmacology; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D016716:PC12 Cells; D017434:Protein Structure, Tertiary; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D051381:Rats; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D047488:Retinoid X Receptors; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction; D013004:Somatostatin / Q000235:genetics; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology
D017362:Cyclic AMP Response Element-Binding Protein; D006657:Histones; D009687:Nuclear Proteins; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D013004:Somatostatin; D014212:Tretinoin; D020932:Nerve Growth Factor; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D000123:Acetyltransferases; D050881:E1A-Associated p300 Protein; C494362:Ep300 protein, rat; D051548:Histone Acetyltransferases