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.

Prenatal nicotine exposure leads to decreased histone H3 lysine 9 (H3K9) methylation and increased p66shc expression in the neonatal pancreas

2021 ◽  
pp. 1-5
Author(s):  
Sergio Raez-Villanueva ◽  
Amrita Debnath ◽  
Daniel B. Hardy ◽  
Alison C. Holloway
Keyword(s):  
Pancreatic Beta Cells ◽  
Histone H3 ◽  
Adverse Outcomes ◽  
Beta Cell Apoptosis ◽  
Nicotine Exposure ◽  
Nicotine Treatment ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase ◽  
Prenatal Nicotine

Abstract Prenatal exposure to nicotine, tobacco’s major addictive constituent, has been shown to reduce birth weight and increases apoptosis, oxidative stress, and mitochondrial dysfunction in the postnatal pancreas. Given that upregulated levels of the pro-oxidative adapter protein p66shc is observed in growth-restricted offspring and is linked to beta-cell apoptosis, the goal of this study was to investigate whether alterations in p66shc expression underlie the pancreatic deficits in nicotine-exposed offspring. Maternal administration of nicotine in rats increased p66shc expression in the neonatal pancreas. Similarly, nicotine treatment augmented p66shc expression in INS-1E pancreatic beta cells. Increased p66shc expression was also associated with decreased histone H3 lysine 9 methylation. Finally, nicotine increased the expression of Kdm4c, a key histone lysine demethylase, and decreased Suv39h1, a critical histone lysine methyltransferase. Collectively, these results suggest that upregulation of p66shc through posttranslational histone modifications may underlie the reported adverse outcomes of nicotine exposure on pancreatic function.

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 The H3K9 Methylation Writer SETDB1 and its Reader MPP8 Cooperate to Silence Satellite DNA Repeats in Mouse Embryonic Stem Cells

Genes ◽  
2019 ◽  
Vol 10 (10) ◽  
pp. 750 ◽  
Author(s):  
Cruz-Tapias ◽  
Robin ◽  
Pontis ◽  
Maestro ◽  
Ait-Si-Ali
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Dna Repeats ◽  
H3k9 Methylation ◽  
Set Domain ◽  
Histone Lysine Methyltransferase ◽  
Satellite Repeats ◽  
M Phase ◽  
Lysine Methyltransferase

SETDB1 (SET Domain Bifurcated histone lysine methyltransferase 1) is a key lysine methyltransferase (KMT) required in embryonic stem cells (ESCs), where it silences transposable elements and DNA repeats via histone H3 lysine 9 tri-methylation (H3K9me3), independently of DNA methylation. The H3K9 methylation reader M-Phase Phosphoprotein 8 (MPP8) is highly expressed in ESCs and germline cells. Although evidence of a cooperation between H3K9 KMTs and MPP8 in committed cells has emerged, the interplay between H3K9 methylation writers and MPP8 in ESCs remains elusive. Here, we show that MPP8 interacts physically and functionally with SETDB1 in ESCs. Indeed, combining biochemical, transcriptomic and genomic analyses, we found that MPP8 and SETDB1 co-regulate a significant number of common genomic targets, especially the DNA satellite repeats. Together, our data point to a model in which the silencing of a class of repeated sequences in ESCs involves the cooperation between the H3K9 methylation writer SETDB1 and its reader MPP8.

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 Gfi1 Coordinates Epigenetic Repression of p21Cip/WAF1 by Recruitment of Histone Lysine Methyltransferase G9a and Histone Deacetylase 1

2005 ◽  
Vol 25 (23) ◽  
pp. 10338-10351 ◽  
Author(s):  
Zhijun Duan ◽  
Adrian Zarebski ◽  
Diego Montoya-Durango ◽  
H. Leighton Grimes ◽  
Marshall Horwitz
Keyword(s):  
Cell Fate ◽  
Histone Deacetylase ◽  
Histone H3 ◽  
Hematopoietic Stem ◽  
Histone Deacetylase 1 ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase ◽  
Cell Processes ◽  
Epigenetic Repression

ABSTRACT The growth factor independent 1 (Gfi1) transcriptional regulator oncoprotein plays a crucial role in hematopoietic, inner ear, and pulmonary neuroendocrine cell development and governs cell processes as diverse as self-renewal of hematopoietic stem cells, proliferation, apoptosis, differentiation, cell fate specification, and oncogenesis. However, the molecular basis of its transcriptional functions has remained elusive. Here we show that Gfi1 recruits the histone lysine methyltransferase G9a and the histone deacetylase 1 (HDAC1) in order to modify the chromatin of genes targeted for repression by Gfi1. G9a and HDAC1 are both in a repressive complex assembled by Gfi1. Endogenous Gfi1 colocalizes with G9a, HDAC1, and K9-dimethylated histone H3. Gfi1 associates with G9a and HDAC1 on the promoter of the cell cycle regulator p21 Cip/WAF1 , resulting in an increase in K9 dimethylation at histone H3. Silencing of Gfi1 expression in myeloid cells reverses G9a and HDAC1 recruitment to p21 Cip/WAF1 and elevates its expression. These findings highlight the role of epigenetics in the regulation of development and oncogenesis by Gfi1.

scholarly journals Selective Interactions between Vertebrate Polycomb Homologs and the SUV39H1 Histone Lysine Methyltransferase Suggest that Histone H3-K9 Methylation Contributes to Chromosomal Targeting of Polycomb Group Proteins

2002 ◽  
Vol 22 (15) ◽  
pp. 5539-5553 ◽  
Author(s):  
Richard G. A. B. Sewalt ◽  
Monika Lachner ◽  
Mark Vargas ◽  
Karien M. Hamer ◽  
Jan L. den Blaauwen ◽  
...  
Keyword(s):  
Histone H3 ◽  
Histone Deacetylation ◽  
Polycomb Group ◽  
Gene Activity ◽  
Chromosome 1 ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase

ABSTRACT Polycomb group (PcG) proteins form multimeric chromatin-associated protein complexes that are involved in heritable repression of gene activity. Two distinct human PcG complexes have been characterized. The EED/EZH2 PcG complex utilizes histone deacetylation to repress gene activity. The HPC/HPH PcG complex contains the HPH, RING1, BMI1, and HPC proteins. Here we show that vertebrate Polycomb homologs HPC2 and XPc2, but not M33/MPc1, interact with the histone lysine methyltransferase (HMTase) SUV39H1 both in vitro and in vivo. We further find that overexpression of SUV39H1 induces selective nuclear relocalization of HPC/HPH PcG proteins but not of the EED/EZH2 PcG proteins. This SUV39H1-dependent relocalization concentrates the HPC/HPH PcG proteins to the large pericentromeric heterochromatin domains (1q12) on human chromosome 1. Within these PcG domains we observe increased H3-K9 methylation. Finally, we show that H3-K9 HMTase activity is associated with endogenous HPC2. Our findings suggest a role for the SUV39H1 HMTase and histone H3-K9 methylation in the targeting of human HPC/HPH PcG proteins to modified chromatin structures.

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
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