Although histone methylation is known to regulate gene transcription through chromatin modification, no transcription factor has yet been identified as a direct target for methylation. In Science, however, Evans and colleagues now describe a unique molecular switch, which enhances the transcription of nuclear receptor (NR)-dependent genes and blocks the transcription of cyclic-AMP-response-element-binding protein (CREB)-dependent genes. This switch is based on the controlled methylation of histones and the transcriptional cofactors CREB-binding protein (CBP)/p300.

CBP/p300, which possess intrinsic histone acetyltransferase (HAT) activity, and coactivator-associated arginine methyltranferase (CARM1), which has intrinsic histone methyltransferase (HMT) activity, are transcriptional coactivators of NR-dependent genes. Activator of retinoid and thyroid receptors (ACTR) is a cofactor that also possesses HAT activity and interacts with both CBP/p300 and CARM1.

Evans and co-workers used an in vitro chromatin-based NR-dependent transcription system to characterize the interplay between the p300- HAT and CARM1-HMT activities. They observed the most striking transcriptional enhancement in the presence of p300, CARM1 and ACTR, indicating that a trimeric coactivator complex might be required for maximal activation of NR-dependent genes.

Using a CARM1-HMT-defective mutant, the authors showed that this HMT activity is essential for the observed enhancement of NR-dependent transcription. They also showed that p300-acetylated histones are more effectively methylated by CARM1 than are nonacetylated histones, indicating that CARM1 might be an NR cofactor through which acetylation and methylation cooperate to modify chromatin and stimulate transcription.

The authors used a similar system to analyse the effect of CARM1 on CREB-dependent transcription. Although CBP/p300 enhance this transcription, CARM1 inhibits it, and this inhibition was not observed using a CARM1-HMT-defective mutant. Evans and colleagues found that, in addition to methylating histones, CARM1 also specifically methylates CBP/p300.

As CREB-dependent transcription is determined by the strength of the interaction between the KIX domain of CBP/p300 and the kinase-inducible domain (KID) of CREB, The authors proposed that CARM1-dependent methylation of CBP/p300 inhibits CREB signalling by disrupting this interaction.

To identify the site on CBP/p300 that is methylated by CARM1, the authors did in vitro methylation assays using GST–KIX fusion proteins with mutations in various arginine residues. They found that CARM1 predominantly methylates a single arginine residue in CBP and p300 that is localized to the external surface of the KIX–KID complex. Methylation of this site disrupts the formation of this complex, but does not affect the NR-related functions of CBP/p300.

Evans and colleagues identified a potential physiological role for CARM1 when they showed that CARM1 induces apoptosis in neuronal cells in vivo. Nerve growth factor promotes the survival of neurons by inducing CREB-dependent expression of Bcl-2 — an anti-apoptotic factor — in neuronal cells. The authors showed that this CARM1-induced apoptosis was dependent on CARM1-HMT activity and was linked to the inhibition of Bcl-2 induction.

Methylation by CARM1 serves as a unique transcriptional switch, as it can activate the expression of NR-dependent genes, whilst inhibiting the expression of CREB-dependent genes. This study is the first report of direct methylation of a transcriptional cofactor, and, as CREB-dependent signalling pathways are developmentally and physiologically important, methylation by CARM1 could turn out to have very broad biological implications.