Biology subjects

Kook, H.

Publications and source records attributed to Kook, H..

3 recordsLinked to original sources

bioRxiv2020

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

Demethylation of histone lysines, one of the most important modifications in transcriptional regulation, is associated with various physiological states. KDM2B is a histone H3K4, H3K36, and H3K79 demethylase associated with the repression of transcription. Here, we present a novel mechanism by which KDM2B demethylates serum response factor (SRF) K165 to negatively regulate muscle differentiation, which is counteracted by histone methyltransferase SET7. We show that KDM2B inhibited skeletal muscle differentiation by inhibiting the transcription of SRF-dependent genes. Both KDM2B and SET7 regulated the balance of SRF K165 methylation. SRF K165 methylation was required for the transcriptional activation of SRF and for the promoter occupancy of SRF-dependent genes. SET7 inhibitors blocked muscle cell differentiation. Taken together, these data indicate that SRF is a non-histone target of KDM2B and that the methylation balance of SRF maintained by KDM2B and SET7 plays an important role in muscle cell differentiation.

developmental biology↗

bioRxiv2019

Cardiac nitric oxide synthase 1 worsens heart failure with preserved ejection fraction through S-nitrosylation of histone deacetylase 2

Although the clinical importance of heart failure with preserved ejection fraction (HFpEF), which makes up half of heart failure, has been extensively explored, most therapeutic regimens, including nitric oxide (NO) donors, lack therapeutic benefit1-12. Here we report that neuronal nitric oxide synthase (nNOS, also known as NOS1) induces HFpEF by S-nitrosylation of histone deacetylase 2 (HDAC2). HFpEF animal models--SAUNA (SAlty drinking water/Unilateral Nephrectomy/Aldosterone)13,14 and mild transverse aortic constriction (TAC) mice14,15--showed increased nNOS expression and NO production, which resulted in the S-nitrosylation of HDAC2. HFpEF was alleviated in S-nitrosylation-dead HDAC2 knock-in mice. Pharmacologic intervention by either nNOS inhibition or HDAC2 denitrosylation attenuated HFpEF. Our observations are the first to demonstrate a completely new mechanistic aspect in HFpEF, which may provide a novel therapeutic approach to HFpEF. In addition, our results provide evidence for why conventional NO-enhancement trials have not been effective for improving HFpEF.

molecular biology↗

bioRxiv2017

KDM2B is a histone H3K79 demethylase and induces transcriptional repression via SIRT1-mediated chromatin silencing

The methylation of histone H3 lysine 79 (H3K79) is an active chromatin marker and is prominant 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), a member of the Jumonji C family of proteins and known for its histone H3K36 demethylase activity, is a di- and tri-methyl 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, indicating that KDM2B functions as an H3K79 demethylase in vivo. Finally, stable KDM2B-knockdown cell lines exhibit displacement of NAD+-dependent deacetylase 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.

genetics↗