KDM2B is a histone H3K79 demethylase and induces transcriptional repression via sirtuin‐1‐mediated chromatin silencing

ABSTRACT The methylation of histone H3 lysine 79 (H3K79) is an active chromatin marker and is prominent in actively transcribed regions of the genome; however, demethylase of H3K79 remains unknown despite intensive research. Here, we show that KDM2B, also known as FBXL10 and a member of the Jumonji C family of proteins known for its histone H3K36 demethylase activity, is a di‐ and trimethyl H3K79 demethylase. We demonstrate that KDM2B induces transcriptional repression of HOXA7and MEIS1 via occupancy of promoters and demethylation of H3K79. Furthermore, genome‐wide analysis suggests that H3K79 methylation levels increase when KDM2B is depleted, which indicates that KDM2B functions as an H3K79 demethylase in vivo. Finally, stable KDM2B‐ knockdown cell lines exhibit displacement of NAD+‐dependent deacetylase sirtuin‐1 (SIRT1) from chromatin, with concomitant increases in H3K79 methylation and H4K16 acetylation. Our findings identify KDM2B as an H3K79 demethylase and link its function to transcriptional repression via SIRT1‐mediated chromatin silencing.—Kang, J.‐Y., Kim, J.‐Y., Kim, K.‐B., Park, J. W., Cho, H., Hahm, J. Y., Chae, Y.‐C., Kim, D., Kook, H., Rhee, S., Ha, N.‐C., Seo, S.‐B. KDM2B is a histone H3K79 demethylase and induces transcriptional repression via sirtuin‐1‐mediated chromatin silencing. FASEB J. 32, 5737–5750 (2018). www.fasebj.org