Epigenetics meets estrogen receptor: regulation of estrogen receptor by direct lysine methylation

Abstract

The nuclear hormone receptor estrogen receptor α (ERα) promotes cellular growth through ligand-dependent activation of specific target genes, a process which is targeted in the treatment of ERα-expressing breast cancers. ERα activity is regulated at the protein level by post-translational modifications including phosphorylation and acetylation. A study now shows that ERα can also be directly methylated at lysine 302 (K302) by SET7, a histone methyltransferase that is known to monomethylate H3K4 and is associated with transcriptional activation. It was shown that K302 methylation stabilizes ERα protein and is suggested to increase sensitivity of ERα to estrogens, enhancing transcription of estrogen response elements. Furthermore, SET7 methylation of K302 is enhanced by a breast cancer-associated mutation at K303 (K303R) in vitro. These findings provide an additional mechanism of SET7 mediated transcriptional activation, as well as potential insight into the complex regulation of ERα stability and ligand sensitivity.

Figure 1

Post-translational modifications of ERα. The subdomains of ERα are outlined with some of the major previously identified PTMs annotated with numbered shapes (defined in legend). (A) The major functional domains of ERα are shown. The poorly conserved AF-1 domain lies at the N-terminus, followed by the DNA binding domain (DBD). The C-terminal region of ERα houses the ligand-binding domain (LBD) of hormone receptors which contains the well-conserved AF-2 domain. (B) The DNA and ligand binding regions are connected by the hinge region, expanded to show the various PTM target residues previously identified. (C) Comparison of the SET7 binding motif for the hinge region of ERα, TAF10, p53, and histone h3 is shown. The recognition consensus sequence is shaded in grey with the target lysine residues aligned and in bold. The PTMs highlighted above were reported in the following publications: 1, (Ali et al. 1993), 2, (Cui et al. 2004), 3, (Kim et al. 2006), 4, (Sentis et al. 2005), 5, (Berry et al. 2008), 6, (Subramanian et al. 2008).

Figure 2

SET7 methylates multiple target proteins to activate transcription. H3K4 methylation by SET7 facilitates gene transcription by preventing chromatin condensation, while SET7 methylation of transcription factors such as p53, TAF10, and ERα enhances their ability to serve as transcriptional activators.