Genome-wide Profiling of Epigenetic Status of SUMO and Transcription Regulation

Herpesviruses exhibits both latent (heterochromatin state) and lytic phase (euchromatin state). They have long served as model systems to elucidate gene regulation and chromatin remodelling due to their ease of manipulation the conversions between these two phases. We chose KSHV, a γ-herpesvirus, as a model to study the functional role of Small ubiquitin-like modifier (SUMO) in regulating the interchange between heterochromatin and euchromatin. SUMO is a reversible post-translational modification involved in virtually all cellular processes including epigenetic regulation of transcription. Higher eukaryotes possess two groups of SUMO conjugating variants; SUMO-1 and SUMO-2/3. We used ChIP-Seq, a technology which allows the direct identification of protein binding sites on chromatin, in conjunction with RNA-seq in K-Rta-induced BCBL-1 cells. We found that SUMO-2/3 modifications significantly increased in promoter regions of transcriptionally active genes and these genes do not undergo changes in transcription level during viral reactivation. Gene ontology analysis suggests that those SUMO-2/3 targeted genes are preferentially in immune pathways. This suggests that SUMO-2/3, but not SUMO-1, ensures the steady-state expression of host genes without overt activation during viral reactivation. Interestingly, most of the SUMO-2/3 increased regions were aligned well with the coating regions of histone lysine demethylase JMJD2A on KSHV genome. In line with our previous report showing that K-bZIP, the first viral SUMO E3 ligase we recently identified, can directly interact with JMJD2A and inhibit its function. These results suggest the potential role of SUMOylation in regulating histone modification enzymes in mediating global gene shutoff.