Suv39h-Mediated Histone H3 Lysine 9 Methylation Directs DNA Methylation to Major Satellite Repeats at Pericentric Heterochromatin
Current BiologyPublished 1 July 2003Open access
Bernhard Lehnertz, Yoshihide Ueda, Alwin A.H.A. Derijck, Ulrich Braunschweig, Laura Perez-Burgos, Stefan Kubicek
Citations1,228
SJR quartileQ1
SJR score2.71
SNIP1.83
Generate an AI Snapshot to get a quick, structured summary of this paper.
Study Snapshot
ObjectiveStudy objective
MethodsResearch methodology
PopulationPopulation studied
Sample sizeSample sizes
OutcomesStudy outcomes here
ResultsStudy results comes here
LimitationsResearch study limitations comes here
A concise AI-generated summary of the paper will appear here once you click Generate AI Snapshot.
TL;DR
An evolutionarily conserved pathway between histone H3-K9 methylation and DNA methylation in mammals is demonstrated and both methylation systems are likely to be important in reinforcing the stability of heterochromatic subdomains and thereby in protecting genome integrity.
Abstract
These data demonstrate an evolutionarily conserved pathway between histone H3-K9 methylation and DNA methylation in mammals. While the Suv39h HMTases are required to direct H3-K9 trimethylation and Dnmt3b-dependent DNA methylation at pericentric repeats, DNA methylation at centromeric repeats occurs independent of Suv39h function. Thus, our data also indicate a more complex interrelatedness between histone and DNA methylation systems in mammals. Both methylation systems are likely to be important in reinforcing the stability of heterochromatic subdomains and thereby in protecting genome integrity.
Keywords
Agricultural and Biological SciencesBiochemistry, Genetics and Molecular Biology
Genes & DevelopmentDNA methylation patterns and epigenetic memory
7,001 Citations2002Adrian Bird
The heritability of methylation states and the secondary nature of the decision to invite or exclude methylation support the idea that DNA methylation is adapted for a specific cellular memory function in development.
CellDNA Methyltransferases Dnmt3a and Dnmt3b Are Essential for De Novo Methylation and Mammalian Development
6,082 Citations1999Masaki Okano, Daphne W. Bell +2 more
It is demonstrated that two recently identified DNA methyltransferases, DnMT3a and Dnmt3b, are essential for de novo methylation and for mouse development and play important roles in normal development and disease.
CellTargeted mutation of the DNA methyltransferase gene results in embryonic lethality
3,960 Citations1992En Li, Timothy H. Bestor +1 more
Results indicate that while a 3-fold reduction in levels of genomic m5C has no detectable effect on the viability or proliferation of ES cells in culture, a similar reduction of DNA methylation in embryos causes abnormal development and embryonic lethality.
NatureTranscriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex
3,432 Citations1998Xinsheng Nan, Huck‐Hui Ng +5 more
The data suggest that two global mechanisms of gene regulation, DNA methylation and histone deacetylation, can be linked by MeCP2, an abundant nuclear protein that is essential for mouse embryogenesis.
NatureSelective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain
2,860 Citations2001Andrew J. Bannister, Philip Zegerman +5 more
A stepwise model for the formation of a transcriptionally silent heterochromatin is provided: SUV39H1 places a ‘methyl marker’ on histone H3, which is then recognized by HP1 through its chromo domain, which may also explain the stable inheritance of theheterochromatic state.
NatureMethylation of histone H3 lysine 9 creates a binding site for HP1 proteins
2,829 Citations2001Monika Lachner, Dónal O’Carroll +3 more
It is shown that mammalian methyltransferases that selectively methylate histone H3 on lysine 9 (Suv39h HMTases) generate a binding site for HP1 proteins—a family of heterochromatic adaptor molecules implicated in both gene silencing and supra-nucleosomal chromatin structure.
Nature GeneticsMethylated DNA and MeCP2 recruit histone deacetylase to repress transcription
2,728 Citations1998Peter Lloyd Jones, Gert Jan C. Veenstra +6 more
The results establish a direct causal relationship between DNA methylation-dependent transcriptional silencing and the modification of chromatin.
ScienceRegulation of Heterochromatic Silencing and Histone H3 Lysine-9 Methylation by RNAi
2,074 Citations2002Thomas A. Volpe, Catherine Kidner +4 more
It is proposed that double-stranded RNA arising from centromeric repeats targets formation and maintenance of heterochromatin through RNAi.
CellLoss of the Suv39h Histone Methyltransferases Impairs Mammalian Heterochromatin and Genome Stability
1,754 Citations2001Antoine H.F.M. Peters, Dónal O’Carroll +12 more
In vivo data assign a crucial role for pericentric H3-K9 methylation in protecting genome stability, and define the Suv39h HMTases as important epigenetic regulators for mammalian development.
ScienceRole of Histone H3 Lysine 9 Methylation in Epigenetic Control of Heterochromatin Assembly
1,742 Citations2001Jun‐ichi Nakayama, Judd C. Rice +3 more
In vivo evidence is provided that lysine 9 of histone H3 (H3 Lys9) is preferentially methylated by the Clr4 protein at heterochromatin-associated regions in fission yeast, defining a conserved pathway wherein sequential histone modifications establish a “histone code” essential for the epigenetic inheritance of heterochROMatin assembly.
CellPurification, sequence, and cellular localization of a novel chromosomal protein that binds to Methylated DNA
1,372 Citations1992Joe Lewis, Richard R. Meehan +5 more
This work reports the identification, purification, and cDNA cloning of a novel MeCP called MeCP2, which unlike MeCP1, the new protein is able to bind to DNA that contains a single methyl-CpG pair.
CellMeCP2 Is a Transcriptional Repressor with Abundant Binding Sites in Genomic Chromatin
1,291 Citations1997Xinsheng Nan, Francisco J. Campoy +1 more
Transient transfection using fusions with the GAL4 DNA binding domain identified a region of MeCP2 that is capable of long-range repression in vivo and suggest a role as a global transcriptional repressor in vertebrate genomes.
NatureControl of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase
1,249 Citations2002James P. Jackson, Anders M. Lindroth +2 more
The isolation of KRYPTONITE, a methyltransferase gene specific to H3 Lys 9, identified in a mutant screen for suppressors of gene silencing at the Arabidopsis thaliana SUPERMAN (SUP) locus is reported, which suggests that CpNpG DNA methylation is controlled by histone H 3 Lys 9 methylation, through interaction of CMT3 with methylated chromatin.
NatureChromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene
1,194 Citations1999Guoliang Xu, Timothy H. Bestor +8 more
It is shown that five unrelated ICF patients have mutations in both alleles of the gene that encodes DNA methyltransferase 3B (refs 5, 6), which is the only genetic disorder known to involve constitutive abnormalities of genomic methylation patterns.
Molecular CellThe Histone Variant H3.3 Marks Active Chromatin by Replication-Independent Nucleosome Assembly
1,113 Citations2002Kami Ahmad, Steven Henikoff
A mechanism of chromatin regulation whereby the variant H3.3 is deposited at particular loci, including active rDNA arrays, providing a mechanism for the immediate activation of genes that are silenced by histone modification.
Nature Reviews GeneticsDNA methylation in health and disease
1,059 Citations2000Keith D. Robertson, Alan P. Wolffe
DNA methylation has recently moved to centre stage in the aetiology of human neurodevelopmental syndromes such as the fragile X, ICF and Rett Syndromes, and understanding this link will be central to the design of new therapeutic tools.
NatureA histone H3 methyltransferase controls DNA methylation in Neurospora crassa
1,039 Citations2001Hisashi Tamaru, Eric U. Selker
It is demonstrated that recombinant DIM-5 protein specifically methylates histone H3 and that replacement of lysine 9 in hist one H3 with either a leucine or an arginine phenocopies the dim-5 mutation, concluding that DNA methylation depends on histone methylation.
Nature GeneticsDNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci
1,022 Citations2000Michael R. Rountree, Kurtis E. Bachman +1 more
DNMT1 not only maintains DNA methylation, but also may directly target, in a heritable manner, transcriptionally repressive chromatin to the genome during DNA replication.
Journal of Biological ChemistryThe Methyl-CpG-binding Protein MeCP2 Links DNA Methylation to Histone Methylation
986 Citations2003François Fuks, Paul J. Hurd +4 more
It is shown that MeCP2 associates with histone methyltransferase activity in vivo and that this activity is directed against Lys9 of histone H3, and this activity coincides with an increase in H3 Lys9methylation.
ScienceEstablishment and Maintenance of a Heterochromatin Domain
910 Citations2002Ira M. Hall, Gurumurthy D. Shankaranarayana +4 more
It is demonstrated that a centromere-homologous repeat present at the silent mating-type region is sufficient for heterochromatin formation at an ectopic site, and that its repressive capacity is mediated by components of the RNA interference (RNAi) machinery.
ScienceHuman DNA-(Cytosine-5) Methyltransferase-PCNA Complex as a Target for p21 <sup>WAF1</sup>
894 Citations1997Linda S.-H. Chuang, Hang-In Ian +4 more
DNA-(cytosine-5) methyltransferase (MCMT) methylates newly replicated mammalian DNA, but the factors regulating this activity are unknown, and MCMT is shown to bind proliferating cell nuclear antigen (PCNA), an auxiliary factor for DNA replication and repair.
DevelopmentDe novo DNA cytosine methyltransferase activities in mouse embryonic stem cells
802 Citations1996Hong Lei, S. Paul Oh +5 more
A null mutation of the only known mammalian DNA methyltransferase gene is generated in mouse embryonic stem cells and it is found that the development of the homozygous embryos is arrested prior to the 8-somite stage, suggesting the existence of a second DNA methyl transferase in mammalian cells.
Nature GeneticsMaintenance of genomic methylation requires a SWI2/SNF2-like protein
700 Citations1999Jeffrey A. Jeddeloh, Trevor Stokes +1 more
It is reported that DDM1 encodes a SWI2/SNF2-like protein, implicating chromatin remodelling as an important process for maintenance of DNA methylation and genome integrity.
Nature GeneticsMutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation
492 Citations2000Richard J. Gibbons, Tarra L. McDowell +5 more
Current BiologyInterplay between Two Epigenetic Marks
472 Citations2002Lianna M. Johnson, Xiaofeng Cao +1 more
It is proposed that loss of H3-K9 methylation is due to transcriptional reactivation, coupled with deposition of unmethylated nucleosomes, consistent with recent observations of DNA replication-independent deposition of histone H3.3 in Drosophila.
ScienceDependence of Heterochromatic Histone H3 Methylation Patterns on the <i>Arabidopsis</i> Gene <i>DDM1</i>
436 Citations2002Anne-Valérie Gendrel, Zachary B. Lippman +3 more
The results suggest that transposon methylation may be guided by histone H3 methylation in plant genomes, which would account for the epigenetic inheritance of hypomethylated DNA once histone Lysine 4 methylation patterns are altered.
Journal of Biological ChemistryDnmt3a and Dnmt3b Are Transcriptional Repressors That Exhibit Unique Localization Properties to Heterochromatin
434 Citations2001Kurtis E. Bachman, Michael R. Rountree +1 more
It is demonstrated that the recently identified DNA methyltransferases, DnMT3a and Dnmt3b, like DNMT1, repress transcription in a methylation-independent manner and are important to the fact that mutations in DNMT3B are found in the developmental syndrome, ICF (immunodeficiency, centromeric heterochromatin instability, and facial anomalies).
PubMedHistone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2'-deoxycytidine.
384 Citations2002Carvell T. Nguyen, Daniel J. Weisenberger +5 more
Using the chromatin immunoprecipitation (ChIP) assay, it is demonstrated that aberrantly silenced genes in cancer cells exhibit a heterochromatic structure that is characterized by histone H3 lysine 9 (H3-K9) hypermethylation and histone Lysine 4 (H 3-K4) hypomethylation, which may play a role in the silencing of tumor-suppressor genes incancer.
Genes & DevelopmentLsh, a member of the SNF2 family, is required for genome-wide methylation
382 Citations2001Kathleen Dennis, Tao Fan +3 more
It is reported here, however, that Lsh(-/-) mice show substantial loss of methylation throughout the genome, which suggests that global genomic methylation is not absolutely required for normal embryogenesis.
Journal of Biological ChemistryA Novel Dnmt3a Isoform Produced from an Alternative Promoter Localizes to Euchromatin and Its Expression Correlates with Activede Novo Methylation
367 Citations2002Taiping Chen, Yoshihide Ueda +2 more
Comparison of human embryonal carcinoma cell lines with breast/ovarian cancer cell lines indicates that DNMT3A2 expression correlates with high de novo methylation activity, suggesting that Dnmt3a and DnMT3a2 may have distinct DNA targets and different functions in development.
PubMedDependence of histone modifications and gene expression on DNA hypermethylation in cancer.
358 Citations2002Jill A. Fahrner, Sayaka Eguchi +2 more
It is shown that a zone of deacetylated histone H3 plus methyl-H3-K9 surrounds a hypermethylated, silenced hMLH1 promoter, which, when unmethylated and active, is embedded in methyl- H3- K4 and acetylated H3.
Journal of Molecular BiologyDNA (cytosine-5)-methyltransferases in mouse cells and tissues. studies with a mechanism-based probe
356 Citations1997Jeffrey A. Yoder, Neilesh S. Soman +2 more
Data suggest that any sequence-specific de novo methylation mediated by Dnmt1 is either under the control of regulatory factors that interact with DnMT1, or is cued by alternative secondary structures in DNA.
Molecular and Cellular BiologyCritical Role of Histone Methylation in Tumor Suppressor Gene Silencing in Colorectal Cancer
346 Citations2002Yutaka Kondo, Lanlan Shen +1 more
Molecular and Cellular BiologyDNA Methylation Specifies Chromosomal Localization of MeCP2
342 Citations1996Xinsheng Nan, Peri Tate +2 more
Deletions within MeCP2 showed that localization to heterochromatin required the 85-amino-acid methyl-CpG binding domain but not the remainder of the protein, likely to be a major mediator of downstream consequences of DNA methylation.
Molecular and Cellular BiologyIsolation and Characterization of <i>Suv39h2</i> , a Second Histone H3 Methyltransferase Gene That Displays Testis-Specific Expression
300 Citations2000Dónal O’Carroll, Harry Scherthan +14 more
Immunolocalization of Suv39h2 protein during spermatogenesis indicates enriched distribution at the heterochromatin from the leptotene to the round sperMatid stage, suggesting an additional function of the Suv 39h2 HMTase in organizing meiotic heterochromeatin that may even impart an epigenetic imprint to the male germ line.
Nature GeneticsDejerine–Sottas syndrome associated with point mutation in the peripheral myelin protein 22 (PMP22) gene
255 Citations1993Benjamin B. Roa, P. James B. Dyck +3 more
NatureCell lineage-specific undermethylation of mouse repetitive DNA
223 Citations1984Verne M. Chapman, Lesley M. Forrester +3 more
It is shown that repetitive DNA sequences from all derivatives of the two extraembryonic lineages, trophectoderm and primitive endoderm, are substantially undermethylated compared with primitive ectoderm derivatives, which contrasts with the highly methylated state of these repetitive elements observed in adult somatic tissues.
Molecular and Cellular BiologyStructure-Function Analysis of SUV39H1 Reveals a Dominant Role in Heterochromatin Organization, Chromosome Segregation, and Mitotic Progression
199 Citations2000Martin Melcher, Manfred Schmid +4 more
A dominant role(s) for the SET domain of SUV39H1 in the distribution of prominent heterochromatic proteins is revealed and a possible link between a chromosomal SU(VAR) protein and histone H3 is suggested.
ZOOLOGICAL SCIENCEIsolation and Characterization of<i>pos</i>Mutants Defective in Correct Positioning of Septum in Schizosaccharomyces pombe
182 Citations1996Masaki Edamatsu, Yoko Y. Toyoshima
The results suggest that positional information for cytokinesis are not accurately transmitted to the cell equator, which suggests that the septum positioning is closely related to correct orientation and organization of sePTum.
Current Biologycis-Acting DNA from Fission Yeast Centromeres Mediates Histone H3 Methylation and Recruitment of Silencing Factors and Cohesin to an Ectopic Site
178 Citations2002Janet F. Partridge, Kristin S. Caruana Scott +3 more
Recruitment of Rad21-cohesin underscores the link between heterochromatin and chromatid cohesion and indicates that these centromeric elements act independently of kinetochore activity to recruit cohesin.
GenomicsMouse major (γ) satellite DNA is highly conserved and organized into extremely long tandem arrays: Implications for recombination between nonhomologous chromosomes
126 Citations1989Bryce Vissel, K.H. Andy Choo
It is suggested that the high degree of conservation of the mouse gamma-satellite sequences throughout the mouse genome results from frequent recombinational exchange between nonhomologous chromosomes.