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Albert Jeltsch - One of the best experts on this subject based on the ideXlab platform.
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The SUV39H1 Protein Lysine Methyltransferase Methylates Chromatin Proteins Involved in Heterochromatin Formation and VDJ Recombination
ACS chemical biology, 2017Co-Authors: Srikanth Kudithipudi, Maren Kirstin Schuhmacher, Adam Fiseha Kebede, Albert JeltschAbstract:SUV39H1 is an H3K9 methyltransferase involved in the formation of heterochromatin. We investigated its substrate specificity profile and show recognition of H3 residues between K4 and G12 with highly specific readout of R8. The specificity profile of SUV39H1 is distinct from its paralog SUV39H2, indicating that they can have different additional substrates. Using the specificity profile, several novel SUV39H1 candidate substrates were identified. We observed methylation of 19 novel substrates at the peptide level and for six of them at the protein level. Methylation of RAG2, SET8, and DOT1L was confirmed in cells, which all have important roles in chromatin regulation. Methylation of SET8 allosterically stimulates its H4K20 monomethylation activity connecting SUV39H1 to the generation of increased H4K20me3 levels, another heterochromatic modification. Methylation of RAG2 alters its subnuclear localization, indicating that SUV39H1 might regulate VDJ recombination. Taken together, our results indicate that ...
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Clr4 specificity and catalytic activity beyond H3K9 methylation.
Biochimie, 2017Co-Authors: Denis Kusevic, Srikanth Kudithipudi, Nahid Iglesias, Danesh Moazed, Albert JeltschAbstract:In fission yeast, the catalytic activity of the protein lysine methyltransferase (PKMT) Clr4, the sole homolog of the mammalian SUV39H1 and SUV39H2 enzymes, majorly contributes to the formation of heterochromatin. The enzyme introduces histone 3 lysine 9 (H3K9) di- and tri-methylation, a central heterochromatic histone modification, and later it was also found to methylate the Mlo3 protein, which has a role in heterochromatin formation as well. Herein, we have investigated the substrate specificity of Clr4 using custom made mutational scanning peptide arrays. Our data show, that Clr4 recognizes an RK core motif, showing high preference for R8. In addition, it exhibits specific contacts at the S10, T11, G12 and G13 positions of the H3 peptide recognizing an R-K-SKRT-TCS-G sequence. Based on the specificity profile and in vitro methyltransferase assay targeted searches, 11 putative methylation sites in S. pombe proteins were identified from reported Clr4 interacting proteins including Mlo3. Peptide methylation was observed on Mlo3 and 7 novel target sites with strongest methylation signals on Spbc28F2.11 (HMG box-containing protein) at lysine 292 and Hrp3 (Chromodomain ATP-dep DNA helicase) at lysine 89. These data suggest that Clr4 has additional methylation substrates and it will be important to study the biological function of these novel methylation events. Furthermore, the specificity profile of Clr4 has been used to develop a quantitative method to compare and cluster specificity profiles of PKMTs. It shows that the specificity profile of Clr4 is most similar to that of the SUV39H2 enzyme, one of its human homologs. This approach will be helpful in the comparison of the recognition profiles of other families of PKMTs as well.
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The SUV39H1 Protein Lysine Methyltransferase Methylates Chromatin Proteins Involved in Heterochromatin Formation and VDJ Recombination
2017Co-Authors: Srikanth Kudithipudi, Maren Kirstin Schuhmacher, Adam Fiseha Kebede, Albert JeltschAbstract:SUV39H1 is an H3K9 methyltransferase involved in the formation of heterochromatin. We investigated its substrate specificity profile and show recognition of H3 residues between K4 and G12 with highly specific readout of R8. The specificity profile of SUV39H1 is distinct from its paralog SUV39H2, indicating that they can have different additional substrates. Using the specificity profile, several novel SUV39H1 candidate substrates were identified. We observed methylation of 19 novel substrates at the peptide level and for six of them at the protein level. Methylation of RAG2, SET8, and DOT1L was confirmed in cells, which all have important roles in chromatin regulation. Methylation of SET8 allosterically stimulates its H4K20 monomethylation activity connecting SUV39H1 to the generation of increased H4K20me3 levels, another heterochromatic modification. Methylation of RAG2 alters its subnuclear localization, indicating that SUV39H1 might regulate VDJ recombination. Taken together, our results indicate that beyond the generation of H3K9me3, SUV39H1 has additional roles in chromatin biology by direct stimulation of the establishment of H4K20me3 and the regulation of chromatin binding of RAG2
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Investigation of H2AX methylation by the SUV39H2 protein lysine methyltransferase.
FEBS letters, 2016Co-Authors: Maren Kirstin Schuhmacher, Srikanth Kudithipudi, Albert JeltschAbstract:The H3K9 protein lysine methyltransferase SUV39H2 was reported to methylate K134 of H2AX and stimulate H2AX phosphorylation during DNA damage response [Sone K et al. (2014) Nat Commun 5, 5691]. However, the sequence context of H2AX-K134 differs from the specificity of SUV39H2. We performed in vitro methylation reactions with SUV39H2 (and its homolog SUV39H1) using H2AX protein and peptides, but no methylation at K134 or any other lysine in H2AX was detected. Positive controls demonstrated the functionality of the assays. While our data cannot finally exclude H2AX methylation of SUV39H2 in cells, additional experimental evidence is required to validate this claim.
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Activity and specificity of the human SUV39H2 protein lysine methyltransferase.
Biochimica et biophysica acta, 2014Co-Authors: Maren Kirstin Schuhmacher, Srikanth Kudithipudi, Denis Kusevic, Sara Weirich, Albert JeltschAbstract:Abstract The SUV39H1 and SUV39H2 enzymes introduce H3K9me3, which is essential for the viability of mammalian cells. It was the aim of the present work to investigate the substrate specificity and product pattern of SUV39H2. Methylation of peptide SPOT arrays showed that SUV39H2 recognizes a long motif on H3 comprising T6–K14, with highly specific readout of R8, S10, T11 and G12 and partial specificity at T6, A7, G13 and K14. Modification of R8 and phosphorylation of S10 or T11 lead to a reduction or loss of SUV39H2 activity towards H3K9. The specificity of SUV39H2 differs from other H3K9 PKMTs, like Dim-5 or G9a, and these biochemical differences can be explained by the structures of the corresponding enzymes. Based on the specificity profile we identified additional non-histone candidate substrates in human proteins, but all of them were only weakly methylated by SUV39H2 at the peptide level. We conclude that SUV39H2 displays a high preference for the methylation of H3. Using the catalytic SET domain we show here that the enzyme prefers H3K9me0 as a substrate over H3K9me1 and H3K9me2 and it introduces the first two methyl groups into H3K9me0 in a processive reaction. SUV39H2 can transfer up to three methyl groups to lysine 9 of histone H3 but the last methylation reaction is much slower than the first two steps. We also demonstrate that the N324K mutant in the SET domain of SUV39H2 that has been shown to cause an inherited nasal skin disease in Labrador Retrievers renders SUV39H2 inactive. Differences in the circular dichroism spectra of wild type and mutant proteins indicated that the mutation causes slight structural changes.
Mark E. Cooper - One of the best experts on this subject based on the ideXlab platform.
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Genetic Examination of SETD7 and SUV39H1/H2 Methyltransferases and the Risk of Diabetes Complications in Patients With Type 1 Diabetes
Diabetes, 2011Co-Authors: Anna Syreeni, Assam El-osta, Carol Forsblom, Niina Sandholm, Maikki Parkkonen, Lise Tarnow, Hans Henrik Parving, Amy Mcknight, Alexander P. Maxwell, Mark E. CooperAbstract:OBJECTIVE Hyperglycemia plays a pivotal role in the development and progression of vascular complications, which are the major sources of morbidity and mortality in diabetes. Furthermore, these vascular complications often persist and progress despite improved glucose control, possibly as a result of prior episodes of hyperglycemia. Epigenetic markers mediated by histone methyltransferases are associated with gene activating events that promote enhanced expression of key proinflammatory molecules implicated in vascular injury. In this study, we investigated genetic polymorphisms of the SETD7, SUV39H1, and SUV39H2 methyltransferases as predictors of risk for micro- and macrovascular complications in type 1 diabetes. RESEARCH DESIGN AND METHODS In the Finnish Diabetic Nephropathy Study (FinnDiane) cohort, 37 tagSNPs were genotyped in 2,991 individuals with type 1 diabetes and diabetic retinopathy, diabetic nephropathy, and cardiovascular disease. Seven single nucleotide polymorphisms (SNPs) were genotyped in the replication cohorts from the Steno Diabetes Center and All Ireland/Warren 3/GoKinD U.K. study. RESULTS In a meta-analysis, the minor T allele of the exonic SNP rs17353856 in the SUV39H2 was associated with diabetic retinopathy (genotypic odds ratio 0.75, P = 1.2 × 10 −4 ). The same SNP showed a trend toward an association with diabetic nephropathy as well as cardiovascular disease in the FinnDiane cohort. CONCLUSIONS Our findings propose that a genetic variation in a gene coding for a histone methyltransferase is protective for a diabetic microvascular complication. The pathophysiological implications of this polymorphism or other genetic variation nearby for the vascular complications of type 1 diabetes remain to be investigated.
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genetic examination of setd7 and SUV39H1 h2 methyltransferases and the risk of diabetes complications in patients with type 1 diabetes
Diabetes, 2011Co-Authors: Anna Syreeni, Carol Forsblom, Niina Sandholm, Maikki Parkkonen, Lise Tarnow, Hans Henrik Parving, Alexander P. Maxwell, Assam Elosta, Amy Jayne Mcknight, Mark E. CooperAbstract:OBJECTIVE Hyperglycemia plays a pivotal role in the development and progression of vascular complications, which are the major sources of morbidity and mortality in diabetes. Furthermore, these vascular complications often persist and progress despite improved glucose control, possibly as a result of prior episodes of hyperglycemia. Epigenetic markers mediated by histone methyltransferases are associated with gene activating events that promote enhanced expression of key proinflammatory molecules implicated in vascular injury. In this study, we investigated genetic polymorphisms of the SETD7, SUV39H1, and SUV39H2 methyltransferases as predictors of risk for micro- and macrovascular complications in type 1 diabetes. RESEARCH DESIGN AND METHODS In the Finnish Diabetic Nephropathy Study (FinnDiane) cohort, 37 tagSNPs were genotyped in 2,991 individuals with type 1 diabetes and diabetic retinopathy, diabetic nephropathy, and cardiovascular disease. Seven single nucleotide polymorphisms (SNPs) were genotyped in the replication cohorts from the Steno Diabetes Center and All Ireland/Warren 3/GoKinD U.K. study. RESULTS In a meta-analysis, the minor T allele of the exonic SNP rs17353856 in the SUV39H2 was associated with diabetic retinopathy (genotypic odds ratio 0.75, P = 1.2 × 10 −4 ). The same SNP showed a trend toward an association with diabetic nephropathy as well as cardiovascular disease in the FinnDiane cohort. CONCLUSIONS Our findings propose that a genetic variation in a gene coding for a histone methyltransferase is protective for a diabetic microvascular complication. The pathophysiological implications of this polymorphism or other genetic variation nearby for the vascular complications of type 1 diabetes remain to be investigated.
Srikanth Kudithipudi - One of the best experts on this subject based on the ideXlab platform.
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The SUV39H1 Protein Lysine Methyltransferase Methylates Chromatin Proteins Involved in Heterochromatin Formation and VDJ Recombination
ACS chemical biology, 2017Co-Authors: Srikanth Kudithipudi, Maren Kirstin Schuhmacher, Adam Fiseha Kebede, Albert JeltschAbstract:SUV39H1 is an H3K9 methyltransferase involved in the formation of heterochromatin. We investigated its substrate specificity profile and show recognition of H3 residues between K4 and G12 with highly specific readout of R8. The specificity profile of SUV39H1 is distinct from its paralog SUV39H2, indicating that they can have different additional substrates. Using the specificity profile, several novel SUV39H1 candidate substrates were identified. We observed methylation of 19 novel substrates at the peptide level and for six of them at the protein level. Methylation of RAG2, SET8, and DOT1L was confirmed in cells, which all have important roles in chromatin regulation. Methylation of SET8 allosterically stimulates its H4K20 monomethylation activity connecting SUV39H1 to the generation of increased H4K20me3 levels, another heterochromatic modification. Methylation of RAG2 alters its subnuclear localization, indicating that SUV39H1 might regulate VDJ recombination. Taken together, our results indicate that ...
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Clr4 specificity and catalytic activity beyond H3K9 methylation.
Biochimie, 2017Co-Authors: Denis Kusevic, Srikanth Kudithipudi, Nahid Iglesias, Danesh Moazed, Albert JeltschAbstract:In fission yeast, the catalytic activity of the protein lysine methyltransferase (PKMT) Clr4, the sole homolog of the mammalian SUV39H1 and SUV39H2 enzymes, majorly contributes to the formation of heterochromatin. The enzyme introduces histone 3 lysine 9 (H3K9) di- and tri-methylation, a central heterochromatic histone modification, and later it was also found to methylate the Mlo3 protein, which has a role in heterochromatin formation as well. Herein, we have investigated the substrate specificity of Clr4 using custom made mutational scanning peptide arrays. Our data show, that Clr4 recognizes an RK core motif, showing high preference for R8. In addition, it exhibits specific contacts at the S10, T11, G12 and G13 positions of the H3 peptide recognizing an R-K-SKRT-TCS-G sequence. Based on the specificity profile and in vitro methyltransferase assay targeted searches, 11 putative methylation sites in S. pombe proteins were identified from reported Clr4 interacting proteins including Mlo3. Peptide methylation was observed on Mlo3 and 7 novel target sites with strongest methylation signals on Spbc28F2.11 (HMG box-containing protein) at lysine 292 and Hrp3 (Chromodomain ATP-dep DNA helicase) at lysine 89. These data suggest that Clr4 has additional methylation substrates and it will be important to study the biological function of these novel methylation events. Furthermore, the specificity profile of Clr4 has been used to develop a quantitative method to compare and cluster specificity profiles of PKMTs. It shows that the specificity profile of Clr4 is most similar to that of the SUV39H2 enzyme, one of its human homologs. This approach will be helpful in the comparison of the recognition profiles of other families of PKMTs as well.
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The SUV39H1 Protein Lysine Methyltransferase Methylates Chromatin Proteins Involved in Heterochromatin Formation and VDJ Recombination
2017Co-Authors: Srikanth Kudithipudi, Maren Kirstin Schuhmacher, Adam Fiseha Kebede, Albert JeltschAbstract:SUV39H1 is an H3K9 methyltransferase involved in the formation of heterochromatin. We investigated its substrate specificity profile and show recognition of H3 residues between K4 and G12 with highly specific readout of R8. The specificity profile of SUV39H1 is distinct from its paralog SUV39H2, indicating that they can have different additional substrates. Using the specificity profile, several novel SUV39H1 candidate substrates were identified. We observed methylation of 19 novel substrates at the peptide level and for six of them at the protein level. Methylation of RAG2, SET8, and DOT1L was confirmed in cells, which all have important roles in chromatin regulation. Methylation of SET8 allosterically stimulates its H4K20 monomethylation activity connecting SUV39H1 to the generation of increased H4K20me3 levels, another heterochromatic modification. Methylation of RAG2 alters its subnuclear localization, indicating that SUV39H1 might regulate VDJ recombination. Taken together, our results indicate that beyond the generation of H3K9me3, SUV39H1 has additional roles in chromatin biology by direct stimulation of the establishment of H4K20me3 and the regulation of chromatin binding of RAG2
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Investigation of H2AX methylation by the SUV39H2 protein lysine methyltransferase.
FEBS letters, 2016Co-Authors: Maren Kirstin Schuhmacher, Srikanth Kudithipudi, Albert JeltschAbstract:The H3K9 protein lysine methyltransferase SUV39H2 was reported to methylate K134 of H2AX and stimulate H2AX phosphorylation during DNA damage response [Sone K et al. (2014) Nat Commun 5, 5691]. However, the sequence context of H2AX-K134 differs from the specificity of SUV39H2. We performed in vitro methylation reactions with SUV39H2 (and its homolog SUV39H1) using H2AX protein and peptides, but no methylation at K134 or any other lysine in H2AX was detected. Positive controls demonstrated the functionality of the assays. While our data cannot finally exclude H2AX methylation of SUV39H2 in cells, additional experimental evidence is required to validate this claim.
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Activity and specificity of the human SUV39H2 protein lysine methyltransferase.
Biochimica et biophysica acta, 2014Co-Authors: Maren Kirstin Schuhmacher, Srikanth Kudithipudi, Denis Kusevic, Sara Weirich, Albert JeltschAbstract:Abstract The SUV39H1 and SUV39H2 enzymes introduce H3K9me3, which is essential for the viability of mammalian cells. It was the aim of the present work to investigate the substrate specificity and product pattern of SUV39H2. Methylation of peptide SPOT arrays showed that SUV39H2 recognizes a long motif on H3 comprising T6–K14, with highly specific readout of R8, S10, T11 and G12 and partial specificity at T6, A7, G13 and K14. Modification of R8 and phosphorylation of S10 or T11 lead to a reduction or loss of SUV39H2 activity towards H3K9. The specificity of SUV39H2 differs from other H3K9 PKMTs, like Dim-5 or G9a, and these biochemical differences can be explained by the structures of the corresponding enzymes. Based on the specificity profile we identified additional non-histone candidate substrates in human proteins, but all of them were only weakly methylated by SUV39H2 at the peptide level. We conclude that SUV39H2 displays a high preference for the methylation of H3. Using the catalytic SET domain we show here that the enzyme prefers H3K9me0 as a substrate over H3K9me1 and H3K9me2 and it introduces the first two methyl groups into H3K9me0 in a processive reaction. SUV39H2 can transfer up to three methyl groups to lysine 9 of histone H3 but the last methylation reaction is much slower than the first two steps. We also demonstrate that the N324K mutant in the SET domain of SUV39H2 that has been shown to cause an inherited nasal skin disease in Labrador Retrievers renders SUV39H2 inactive. Differences in the circular dichroism spectra of wild type and mutant proteins indicated that the mutation causes slight structural changes.
Thomas Jenuwein - One of the best experts on this subject based on the ideXlab platform.
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H1 linker histones silence repetitive elements by promoting both histone H3K9 methylation and chromatin compaction.
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Sean E. Healton, Hugo D Pinto, Laxmi N. Mishra, Gregory A. Hamilton, Justin C. Wheat, Kalina Swist-rosowska, Nicholas Shukeir, Yali Dou, Ulrich Steidl, Thomas JenuweinAbstract:Nearly 50% of mouse and human genomes are composed of repetitive sequences. Transcription of these sequences is tightly controlled during development to prevent genomic instability, inappropriate gene activation and other maladaptive processes. Here, we demonstrate an integral role for H1 linker histones in silencing repetitive elements in mouse embryonic stem cells. Strong H1 depletion causes a profound de-repression of several classes of repetitive sequences, including major satellite, LINE-1, and ERV. Activation of repetitive sequence transcription is accompanied by decreased H3K9 trimethylation of repetitive sequence chromatin. H1 linker histones interact directly with SUV39H1, Suv39h2, and SETDB1, the histone methyltransferases responsible for H3K9 trimethylation of chromatin within these regions, and stimulate their activity toward chromatin in vitro. However, we also implicate chromatin compaction mediated by H1 as an additional, dominant repressive mechanism for silencing of repetitive major satellite sequences. Our findings elucidate two distinct, H1-mediated pathways for silencing heterochromatin.
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Oncogene-induced senescence as an initial barrier in lymphoma development
Nature, 2005Co-Authors: Melanie Braig, Cornelia Rudolph, Antoine H. F. M. Peters, Thomas Jenuwein, Christoph Loddenkemper, Bernd Dörken, Harald Stein, Brigitte Schlegelberger, Soyoung Lee, Clemens A. SchmittAbstract:Acute induction of oncogenic Ras provokes cellular senescence involving the retinoblastoma (Rb) pathway, but the tumour suppressive potential of senescence in vivo remains elusive. Recently, Rb-mediated silencing of growth-promoting genes by heterochromatin formation associated with methylation of histone H3 lysine 9 (H3K9me) was identified as a critical feature of cellular senescence, which may depend on the histone methyltransferase SUV39H1. Here we show that Emicro-N-Ras transgenic mice harbouring targeted heterozygous lesions at the SUV39H1, or the p53 locus for comparison, succumb to invasive T-cell lymphomas that lack expression of SUV39H1 or p53, respectively. By contrast, most N-Ras-transgenic wild-type ('control') animals develop a non-lymphoid neoplasia significantly later. Proliferation of primary lymphocytes is directly stalled by a SUV39H1-dependent, H3K9me-related senescent growth arrest in response to oncogenic Ras, thereby cancelling lymphomagenesis at an initial step. SUV39H1-deficient lymphoma cells grow rapidly but, unlike p53-deficient cells, remain highly susceptible to adriamycin-induced apoptosis. In contrast, only control, but not SUV39H1-deficient or p53-deficient, lymphomas senesce after drug therapy when apoptosis is blocked. These results identify H3K9me-mediated senescence as a novel SUV39H1-dependent tumour suppressor mechanism whose inactivation permits the formation of aggressive but apoptosis-competent lymphomas in response to oncogenic Ras.
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epigenetic regulation of telomere length in mammalian cells by the SUV39H1 and suv39h2 histone methyltransferases
Nature Genetics, 2004Co-Authors: Marta Garciacao, Antoine H. F. M. Peters, Thomas Jenuwein, Roderick J Osullivan, Maria A BlascoAbstract:Telomeres are capping structures at the ends of eukaryotic chromosomes composed of TTAGGG repeats bound to an array of specialized proteins1,2,3. Telomeres are heterochromatic regions. Yeast and flies with defects in activities that modify the state of chromatin also have abnormal telomere function4,5,6, but the putative role of chromatin-modifying activities in regulating telomeres in mammals is unknown. Here we report on telomere length and function in mice null with respect to both the histone methyltransferases (HMTases) SUV39H1 and Suv39h2 (called SUV39DN mice). SUV39H1 and Suv39h2 govern methylation of histone H3 Lys9 (H3-Lys9) in heterochromatic regions7. We show that primary cells derived from SUV39DN mice have abnormally long telomeres relative to wild-type controls. Using chromatin immunoprecipitation (ChIP) analysis, we found that telomeres were enriched in di- and trimethylated H3-Lys9 but that telomeres of SUV39DN cells had less dimethylated and trimethylated H3-Lys9 but more monomethylated H3-Lys9. Concomitant with the decrease in H3-Lys9 methylation, telomeres in SUV39DN cells had reduced binding of the chromobox proteins Cbx1, Cbx3 and Cbx5, homologs of Drosophila melanogaster heterochromatin protein 1 (HP1). These findings indicate substantial changes in the state of telomeric heterochromatin in SUV39DN cells, which are associated with abnormal telomere elongation. Taken together, the results indicate epigenetic regulation of telomere length in mammals by SUV39H1 and Suv39h2.
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rb targets histone h3 methylation and hp1 to promoters
Nature, 2001Co-Authors: Soren J Nielsen, Thomas Jenuwein, Donal Ocarroll, Robert Schneider, Utamaria Bauer, Andrew J Bannister, Ashby J Morrison, Ron Firestein, Michael D Cleary, Rafael E HerreraAbstract:In eukaryotic cells the histone methylase SUV39H1 and the methyl-lysine binding protein HP1 functionally interact to repress transcription at heterochromatic sites1. Lysine 9 of histone H3 is methylated by SUV39H1 (ref. 2), creating a binding site for the chromo domain of HP1 (refs 3, 4). Here we show that SUV39H1 and HP1 are both involved in the repressive functions of the retinoblastoma (Rb) protein. Rb associates with SUV39H1 and HP1 in vivo by means of its pocket domain. SUV39H1 cooperates with Rb to repress the cyclin E promoter, and in fibroblasts that are disrupted for SUV39, the activity of the cyclin E and cyclin A2 genes are specifically elevated. Chromatin immunoprecipitations show that Rb is necessary to direct methylation of histone H3, and is necessary for binding of HP1 to the cyclin E promoter. These results indicate that the SUV39H1–HP1 complex is not only involved in heterochromatic silencing but also has a role in repression of euchromatic genes by Rb and perhaps other co-repressor proteins.
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methylation of histone h3 lysine 9 creates a binding site for hp1 proteins
Nature, 2001Co-Authors: Monika Lachner, Stephen Rea, Donal Ocarroll, Karl Mechtler, Thomas JenuweinAbstract:Distinct modifications of histone amino termini, such as acetylation, phosphorylation and methylation, have been proposed to underlie a chromatin-based regulatory mechanism that modulates the accessibility of genetic information. In addition to histone modifications that facilitate gene activity, it is of similar importance to restrict inappropriate gene expression if cellular and developmental programmes are to proceed unperturbed. Here we show 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. High-affinity in vitro recognition of a methylated histone H3 peptide by HP1 requires a functional chromo domain; thus, the HP1 chromo domain is a specific interaction motif for the methyl epitope on lysine9 of histone H3. In vivo, heterochromatin association of HP1 proteins is lost in Suv39h double-null primary mouse fibroblasts but is restored after the re-introduction of a catalytically active SWUV39H1 HMTase. Our data define a molecular mechanism through which the SUV39H-HP1 methylation system can contribute to the propagation of heterochromatic subdomains in native chromatin.
Maria A Blasco - One of the best experts on this subject based on the ideXlab platform.
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Altered telomere homeostasis and resistance to skin carcinogenesis in SUV39H1 transgenic mice.
Cell cycle (Georgetown Tex.), 2015Co-Authors: Eleonora Petti, Maria A Blasco, Fabian Jordi, Valentina Buemi, Roberto Dinami, Roberta Benetti, Stefan SchoeftnerAbstract:The SUV39H1 and Suv39h2 H3K9 histone methyltransferases (HMTs) have a conserved role in the formation of constitutive heterochromatin and gene silencing. Using a transgenic mouse model system we demonstrate that elevated expression of SUV39H1 increases global H3K9me3 levels in vivo. More specifically, SUV39H1 overexpression enhances the imposition of H3K9me3 levels at constitutive heterochromatin at telomeric and major satellite repeats in primary mouse embryonic fibroblasts. Chromatin compaction is paralleled by telomere shortening, indicating that telomere length is controlled by H3K9me3 density at telomeres. We further show that increased SUV39H1 levels result in an impaired clonogenic potential of transgenic epidermal stem cells and Ras/E1A transduced transgenic primary mouse embryonic fibroblasts. Importantly, SUV39H1 overexpression in mice confers resistance to a DMBA/TPA induced skin carcinogenesis protocol that is characterized by the accumulation of activating H-ras mutations. Our results provide genetic evidence that SUV39H1 controls telomere homeostasis and mediates resistance to oncogenic stress in vivo. This identifies SUV39H1 as an interesting target to improve oncogene induced senescence in premalignant lesions.
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Altered telomere homeostasis and resistance to skin carcinogenesis in SUV39H1 transgenic mice.
Cell cycle (Georgetown Tex.), 2015Co-Authors: Eleonora Petti, Maria A Blasco, Fabian Jordi, Valentina Buemi, Roberto Dinami, Roberta Benetti, Stefan SchoeftnerAbstract:The SUV39H1 and Suv39h2 H3K9 histone methyltransferases (HMTs) have a conserved role in the formation of constitutive heterochromatin and gene silencing. Using a transgenic mouse model system we demonstrate that elevated expression of SUV39H1 increases global H3K9me3 levels in vivo. More specifically, SUV39H1 overexpression enhances the imposition of H3K9me3 levels at constitutive heterochromatin at telomeric and major satellite repeats in primary mouse embryonic fibroblasts. Chromatin compaction is paralleled by telomere shortening, indicating that telomere length is controlled by H3K9me3 density at telomeres. We further show that increased SUV39H1 levels result in an impaired clonogenic potential of transgenic epidermal stem cells and Ras/E1A transduced transgenic primary mouse embryonic fibroblasts. Importantly, SUV39H1 overexpression in mice confers resistance to a DMBA/TPA induced skin carcinogenesis protocol that is characterized by the accumulation of activating H-ras mutations. Our results provide...
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epigenetic regulation of telomere length in mammalian cells by the SUV39H1 and suv39h2 histone methyltransferases
Nature Genetics, 2004Co-Authors: Marta Garciacao, Antoine H. F. M. Peters, Thomas Jenuwein, Roderick J Osullivan, Maria A BlascoAbstract:Telomeres are capping structures at the ends of eukaryotic chromosomes composed of TTAGGG repeats bound to an array of specialized proteins1,2,3. Telomeres are heterochromatic regions. Yeast and flies with defects in activities that modify the state of chromatin also have abnormal telomere function4,5,6, but the putative role of chromatin-modifying activities in regulating telomeres in mammals is unknown. Here we report on telomere length and function in mice null with respect to both the histone methyltransferases (HMTases) SUV39H1 and Suv39h2 (called SUV39DN mice). SUV39H1 and Suv39h2 govern methylation of histone H3 Lys9 (H3-Lys9) in heterochromatic regions7. We show that primary cells derived from SUV39DN mice have abnormally long telomeres relative to wild-type controls. Using chromatin immunoprecipitation (ChIP) analysis, we found that telomeres were enriched in di- and trimethylated H3-Lys9 but that telomeres of SUV39DN cells had less dimethylated and trimethylated H3-Lys9 but more monomethylated H3-Lys9. Concomitant with the decrease in H3-Lys9 methylation, telomeres in SUV39DN cells had reduced binding of the chromobox proteins Cbx1, Cbx3 and Cbx5, homologs of Drosophila melanogaster heterochromatin protein 1 (HP1). These findings indicate substantial changes in the state of telomeric heterochromatin in SUV39DN cells, which are associated with abnormal telomere elongation. Taken together, the results indicate epigenetic regulation of telomere length in mammals by SUV39H1 and Suv39h2.
