scholarly journals Expression of SET domain bifurcated histone lysine methyltransferase 1 and its clinical prognostic significance in hepatocellular carcinoma

2021 ◽  
Author(s):  
Chunnian Wang ◽  
Zhaoxia Xia ◽  
Zheng Li ◽  
Fusang Ye ◽  
Shengqiang Ji ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Prognostic Significance ◽  
Set Domain ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase ◽  
Methyltransferase 1

scholarly journals SETD4 Regulates Cell Quiescence and Catalyzes the Trimethylation of H4K20 during Diapause Formation in Artemia

2016 ◽  
Vol 37 (7) ◽  
Author(s):  
Li Dai ◽  
Sen Ye ◽  
Hua-Wei Li ◽  
Dian-Fu Chen ◽  
Hong-Liang Wang ◽  
...  
Keyword(s):  
Quiescent State ◽  
Degenerative Diseases ◽  
Set Domain ◽  
Content Type ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Cell Life ◽  
Cell Quiescence ◽  
Lysine Methyltransferase

ABSTRACT As a prominent characteristic of cell life, the regulation of cell quiescence is important for proper development, regeneration, and stress resistance and may play a role in certain degenerative diseases. However, the mechanism underlying quiescence remains largely unknown. Encysted embryos of Artemia are useful for studying the regulation of this state because they remain quiescent for prolonged periods during diapause, a state of obligate dormancy. In the present study, SET domain-containing protein 4, a histone lysine methyltransferase from Artemia, was identified, characterized, and named Ar-SETD4. We found that Ar-SETD4 was expressed abundantly in Artemia diapause embryos, in which cells were in a quiescent state. Meanwhile, trimethylated histone H4K20 (H4K20me3) was enriched in diapause embryos. The knockdown of Ar-SETD4 reduced the level of H4K20me3 significantly and prevented the formation of diapause embryos in which neither the cell cycle nor embryogenesis ceased. The catalytic activity of Ar-SETD4 on H4K20me3 was confirmed by an in vitro histone methyltransferase (HMT) assay and overexpression in cell lines. This study provides insights into the function of SETD4 and the mechanism of cell quiescence regulation.

scholarly journals Histone lysine methyltransferase SUV39H1 is a potent target for epigenetic therapy of hepatocellular carcinoma

2014 ◽  
Vol 136 (2) ◽  
pp. 289-298 ◽  
Author(s):  
Tetsuhiro Chiba ◽  
Tomoko Saito ◽  
Kaori Yuki ◽  
Yoh Zen ◽  
Shuhei Koide ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epigenetic Therapy ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase

scholarly journals Small Molecule Inhibitors of the Human Histone Lysine Methyltransferase NSD2 / WHSC1 / MMSET Identified from a Quantitative High-Throughput Screen with Nucleosome Substrate

2017 ◽  
Author(s):  
Nathan P. Coussens ◽  
Stephen C. Kales ◽  
Mark J. Henderson ◽  
Olivia W. Lee ◽  
Kurumi Y. Horiuchi ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Point Mutations ◽  
Set Domain ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Attractive Therapeutic Target ◽  
Lysine Methyltransferase ◽  
In Cells

AbstractThe activity of the histone lysine methyltransferase NSD2 is thought to play a driving role in oncogenesis. Both overexpression of NSD2 and point mutations that increase its catalytic activity are associated with a variety of human cancers. While NSD2 is an attractive therapeutic target, no potent, selective and cell-active inhibitors have been reported to date, possibly due to the challenging nature of developing high-throughput assays for NSD2. To establish a platform for the discovery and development of selective NSD2 inhibitors, multiple assays were optimized and implemented. Quantitative high-throughput screening was performed with full-length wild-type NSD2 and a nucleosome substrate against a diverse collection of known bioactives comprising 16,251 compounds. Actives from the primary screen were further interrogated with orthogonal and counter assays, as well as activity assays with the clinically relevant NSD2 mutants E1099K and T1150A. Five confirmed inhibitors were selected for follow-up, which included a radiolabeled validation assay, surface plasmon resonance studies, methyltransferase profiling, and histone methylation in cells. The identification of NSD2 inhibitors that bind the catalytic SET domain and demonstrate activity in cells validates the workflow, providing a template for identifying selective NSD2 inhibitors.

scholarly journals Characterization of SETD3 methyltransferase–mediated protein methionine methylation

2020 ◽  
Vol 295 (32) ◽  
pp. 10901-10910
Author(s):  
Shaobo Dai ◽  
Matthew V. Holt ◽  
John R. Horton ◽  
Clayton B. Woodcock ◽  
Anamika Patel ◽  
...  
Keyword(s):  
Active Site ◽  
Side Chain ◽  
Protein Methylation ◽  
Aromatic Rings ◽  
Set Domain ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Close Proximity ◽  
Lysine Methyltransferase

Most characterized protein methylation events encompass arginine and lysine N-methylation, and only a few cases of protein methionine thiomethylation have been reported. Newly discovered oncohistone mutations include lysine-to-methionine substitutions at positions 27 and 36 of histone H3.3. In these instances, the methionine substitution localizes to the active-site pocket of the corresponding histone lysine methyltransferase, thereby inhibiting the respective transmethylation activity. SET domain–containing 3 (SETD3) is a protein (i.e. actin) histidine methyltransferase. Here, we generated an actin variant in which the histidine target of SETD3 was substituted with methionine. As for previously characterized histone SET domain proteins, the methionine substitution substantially (76-fold) increased binding affinity for SETD3 and inhibited SETD3 activity on histidine. Unexpectedly, SETD3 was active on the substituted methionine, generating S-methylmethionine in the context of actin peptide. The ternary structure of SETD3 in complex with the methionine-containing actin peptide at 1.9 Å resolution revealed that the hydrophobic thioether side chain is packed by the aromatic rings of Tyr312 and Trp273, as well as the hydrocarbon side chain of Ile310. Our results suggest that placing methionine properly in the active site—within close proximity to and in line with the incoming methyl group of SAM—would allow some SET domain proteins to selectively methylate methionine in proteins.

scholarly journals Histone lysine methyltransferase G9a is a novel epigenetic target for the treatment of hepatocellular carcinoma

Oncotarget ◽  
2017 ◽  
Vol 8 (13) ◽  
pp. 21315-21326 ◽  
Author(s):  
Masayuki Yokoyama ◽  
Tetsuhiro Chiba ◽  
Yoh Zen ◽  
Motohiko Oshima ◽  
Yuko Kusakabe ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase

scholarly journals Histone lysine methyltransferase, suppressor of variegation 3-9 homolog 1, promotes hepatocellular carcinoma progression and is negatively regulated by microRNA-125b

Hepatology ◽  
2012 ◽  
Vol 57 (2) ◽  
pp. 637-647 ◽  
Author(s):  
Dorothy Ngo-Yin Fan ◽  
Felice Ho-Ching Tsang ◽  
Aegean Hoi-Kam Tam ◽  
Sandy Leung-Kuen Au ◽  
Carmen Chak-Lui Wong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase

Structure of the SET domain histone lysine methyltransferase Clr4

2002 ◽  
Author(s):  
Jinrong Min ◽  
Xing Zhang ◽  
Xiaodong Cheng ◽  
Shiv I.S. Grewal ◽  
Rui-Ming Xu
Keyword(s):  
Set Domain ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase

scholarly journals SETDB1-Mediated Silencing of Retroelements

Viruses ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 596 ◽  
Author(s):  
Kei Fukuda ◽  
Yoichi Shinkai
Keyword(s):  
Genome Stability ◽  
Histone H3 ◽  
Endogenous Retroviruses ◽  
H3k9 Methylation ◽  
Epigenetic Factors ◽  
Set Domain ◽  
H3k9 Trimethylation ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase

SETDB1 (SET domain bifurcated histone lysine methyltransferase 1) is a protein lysine methyltransferase and methylates histone H3 at lysine 9 (H3K9). Among other H3K9 methyltransferases, SETDB1 and SETDB1-mediated H3K9 trimethylation (H3K9me3) play pivotal roles for silencing of endogenous and exogenous retroelements, thus contributing to genome stability against retroelement transposition. Furthermore, SETDB1 is highly upregulated in various tumor cells. In this article, we describe recent advances about how SETDB1 activity is regulated, how SETDB1 represses various types of retroelements such as L1 and class I, II, and III endogenous retroviruses (ERVs) in concert with other epigenetic factors such as KAP1 and the HUSH complex and how SETDB1-mediated H3K9 methylation can be maintained during replication.

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