Set2-mediated H3K36 methylation ubiquitously functions in coding regions in all eukaryotes. It has been linked to the regulation of acetylation states, histone exchange, alternative splicing, DNA repair and recombination. Set2 is recruited to transcribed chromatin through its SRI domain's direct association with phosphorylated Pol II. However, regulatory mechanisms for histone modifying enzymes like Set2 that travel with elongating Pol II remain largely unknown beyond their initial recruitment events. Here, by fusing Set2 to RNA Pol II, we found that the SRI domain can also recognize linker DNA of chromatin, thereby controlling Set2 substrate specificity. We also discovered that an auto-inhibitory domain (AID) of Set2 primarily restricts Set2 activity to transcribed chromatin and fine-tunes several functions of SRI. Finally, we demonstrated that AID mutations caused hyperactive Set2 in vivo and displayed a synthetic interaction with the histone chaperone FACT. Our data suggest that Set2 is intrinsically regulated through multiple mechanisms and emphasize the importance of a precise temporal control of H3K36 methylation during the dynamic transcription elongation process.
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