Proposed model for the regulation of histone trimethylation by COMPASS through the recruitment of the attachment protein Doa4. The COMPASS methyltransferase protein complex methylates lysine 4 at histone H3 (H3-K4), regulated by ubiquitination of lysine 123 at histone H2B (H2B-K123) [32–35]. H3-K4 can be mono-, di- and tri-methylated and COMPASS is required for all three levels of methylation, while only tri-methylated H3-K4 leads to the activation of gene transcription [39, 40]. The two COMPASS components Spp1 and Bre2 are required for tri-methylation activity of the complex , but both belong to the core of COMPASS (shown in blue) and are present in all isoforms of the complex. The attachment protein Swd2 (orange) mediates the cross-talk between H2B-K123 monoubiquitination and H3-K4 di- and trimethylation . Some isoforms of COMPASS contain the ubiquitin hydrolase Doa4 (magenta) as an attachment, and we thus propose that the addition of the third methyl group (green) to di-methylated H3-K4 by COMPASS is regulated by the recruitment of Doa4 to the complex. Removal of ubiquitin (purple) from H2B-K123 by Doa4 (indicated with scissors) would disrupt the association of Swd2 (orange) with chromatin (histones shown in grey with a black DNA string wrapped around), inhibiting H3-K4 trimethylation.