KDM2B is a histone H3K79 demethylase and induces transcriptional repressionviasirtuin‐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 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.

The inhibition of KDM2B promotes the differentiation of basal-like breast cancer cells via the posttranslational destabilization of SLUG

“…KDM2B (also known as NDY1, FBXL10, JHDM1B or Fbl10), encodes a jumonji C (JmjC) domaincontaining histone lysine demethylase, which targets histone H3K36me2/me1 and perhaps histone H3K4me3 Pfau et al, 2008;Tsukada et al, 2006;Tzatsos et al, 2009) and histone H3K79 me3/me2 (Kang et al, 2018). In addition to the JmjC domain, which is responsible for its demethylase activity , KDM2B contains CXXC and PHD zinc finger domains, an F-box and a leucine-rich repeat Pfau et al, 2008).…”

SRF is a non-histone methylation target of KDM2B and SET7 in the regulation of myogenesis

“…Many researchers, including us, have demonstrated that KDM2B primarily targets histones to demethylate lysine residues (He et al, 2011;Kang et al, 2018;Yan et al, 2018) and that histones H3K4me3 and H3K36me2 in particular can be effectively demethylated (He et al, 2008;Janzer et al, 2012). This raises the possibility that our results showing the inhibition of myogenic transcription factors may result from KDM2B-mediated repressive modification by demethylation at H3K4 and H3K36.…”

“…The JmjC domain catalyzes the demethylation of H3K4me3 and H3K36me2, leading to the transcriptional repression of target genes (He et al, 2008;Janzer et al, 2012). Recently, we also discovered that KDM2B demethylates H3K79 in a sirtuin-1-dependent manner (Kang et al, 2018). KDM2B participates in many aspects of normal cellular processes, such as cell senescence, cell differentiation, and stem cell self-renewal.…”

Epigenetic Regulation of Hepatitis B Virus Replication

“…HBx also increases histone acetylation and H3K4me3 and decreases HP1 binding and H3K9me3 on the cccDNA [24]. Other host transcription factors, mainly suppressors, that act via epigenetic control of HBV include SIRT3 [25], zinc finger and homeoboxes 2 (ZHX2) [26], KDM2B [27], protein arginine methyltransferase 5 (PRMT5) [28], and SETDB1 [24]. Interestingly, mutations in the basal core promoter are also reported to be associated with histone modification [29].…”