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 HOXA7 and 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.
Highlights
Chromatin structure is modulated by diverse covalent histone modifications (Cheung et al, 2000; Strahl and Allis, 2000) Combinations of such modifications direct both global and specific transcriptional outcomes (Berger, 2007; Lee et al, 2010)
By liquid chromatography-tandem mass spectrometry (LC-MS/MS), we showed that methylated H3K79 was associated with chromobox homolog 8 (CBX8), one of the various types of CBX proteins directing the canonical polycomb-repressive complex 1 (PRC1) complex as an interacting component (Figure 1A and B)
We found that RNA interference (RNAi) of endogenous KDM2B led to increased H3K79me[3] and H3K79me[2] levels, but mono-methylation was not affected (Figure 2A, right panel)
Summary
Chromatin structure is modulated by diverse covalent histone modifications (Cheung et al, 2000; Strahl and Allis, 2000) Combinations of such modifications direct both global and specific transcriptional outcomes (Berger, 2007; Lee et al, 2010). Among these modifications, histone lysine methylation is linked to both activation and repression of transcription. Histone H3 lysine 79 methylation (H3K79me) is catalyzed by the HMTase disruptor of telomeric silencing-1 (Dot1)-Like (DOT1L), which is the mammalian homolog of the yeast Dot[1] (Feng et al., 2002; Lacoste et al, 2002; Singer et al, 1998; van Leeuwen et al, 2002). Regulation occurs by trans-crosstalk, and ubiquitylation of histone H2BK123
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