Figure 1. Two fundamentally distinct functions of Spt6 in the regulation of histone modification. (A) Spt6 serves as a transcription machinery-anchored platform for the recruitment of histone modifiers to target loci. Budding yeast Spt6 assists Set2, which interacts with the RNAP II CTD, to trimethylate histone H3 at Lys-36 during transcription (see arrow #1). In mammals, SETD2 is recruited to target loci through interaction with Iws1, a highly conserved Spt6-interacting protein. For demethylation of histone H3, Spt6 recruits JMJD3/KDM6B, KDM6A, and KIAA1718 to target loci (see arrow #2). (B) Spt6 serves as a molecular liaison that prevents cotranscriptional dissociation of preexisting histones H3 and H4. At a minimum, this function is required for the maintenance of histone H3 methylation at Lys-4 and Lys-9 in euchromatin and heterochromatin, respectively. Other posttranslational modifications of histone molecules could also be maintained through this function.