H3K4Me1

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Alexander Von Ruecker - One of the best experts on this subject based on the ideXlab platform.

  • Global histone H4K20 trimethylation predicts cancer‐specific survival in patients with muscle‐invasive bladder cancer
    BJU international, 2011
    Co-Authors: Ann-christin Schneider, Sebastian Rogenhofer, Patrick J. Bastian, Alexander Von Ruecker, Lukas C. Heukamp, Guido Fechner, Stefan Müller, Jörg Ellinger
    Abstract:

    Study Type – Prognosis (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? Epigenetic alterations play an essential role during carcinogenesis. While DNA methylation has been extensively studied in bladder cancer, the relevance of histone modifications remains to be clarified. Earlier studies suggested that global histone modification levels are predictive for patients’ outcome in various tumour entities (e.g. prostate, lung, breast and kidney cancer). The possibility to determine global histone modification levels easily and inexpensively using immunohistochemistry increases a potential routine use in the future. Our aim was therefore to investigate the global levels of histone H3K4 and H4K20 mono-, di- and trimethylation. For this purpose we prepared tissue microarrays with non-muscle-invasive bladder cancer (NMIBC), muscle-invasive bladder cancer (MIBC), bladder cancer metastases (METS) and normal urothelium (NU) tissue to compare global H3K4 and H4K20 methylation in these tissues, as well to assess the prognostic value of histone modifications. We show that global histone modification levels (H3K4Me1, H3K4me3, H4K20me1, H4K20me2, H4K20me3) are lower in bladder cancer than in NU tissue. Furthermore, there was a decrease of histone modification levels (H3K4Me1, H4K20me1, H4K20me2, H4K20me3) from NU over NMIBC and MIBCto METS. Histone modifications are correlated to advanced pathological stage in NMIBC and MIBC. Furthermore, H4K20me3 appeared to be a significant and independent prognostic predictor of bladder cancer-specific survival in patients with MIBC undergoing radical cystectomy. Our findings therefore provide a rationale for further investigation of histone modifications and their manipulation in bladder cancer. OBJECTIVE • To determine the role of global histone methylation as a prognostic parameter in patients with bladder cancer. PATIENTS AND METHODS • We used a tissue microarray with samples from patients with non-muscle-invasive bladder cancer (NMIBC; n= 161), muscle-invasive bladder cancer (MIBC, n= 127), normal urothelium (NU; n= 31) and bladder cancer metastases (METS; n= 31) to determine global histone methylation (me) levels at histone H3 lysine 4 (H3K4) and H4K20. RESULTS • Global histone modification levels (H3K4Me1, H3K4me3, H4K20me1, H4K20me2, and H4K20me3) were lower in bladder cancersamples than in NU tissue • Global levels of H3K4Me1, H4K20me1, H4K20me2 and H4K20me3 were decreasing from NU over NMIBC and MIBC to METS. • H4K20me1 levels were increased in patients with NMIBC with advanced pTstage and less differentiated bladder cancer. • In patients with MIBC, pTstage was negatively correlated with H3K4Me1, H4K20me1 and H4K20me2 levels. • H4K20me3 levels were significantly correlated in a univariate and multivariate model with bladder cancer-specific mortality after radical cystectomy in patients with MIBC. CONCLUSION • Global histone methylation levels may help to identify patients with bladder cancerwith poor prognosis after radical cystectomy.

  • Prognostic relevance of global histone H3 lysine 4 (H3K4) methylation in renal cell carcinoma.
    International journal of cancer, 2010
    Co-Authors: Jörg Ellinger, Philip Kahl, Claudia Mertens, Sebastian Rogenhofer, Stefan Hauser, Wolfgang Hartmann, Patrick J. Bastian, Reinhard Büttner, Stefan C. Müller, Alexander Von Ruecker
    Abstract:

    Epigenetic alterations play an important role in carcinogenesis. Recent studies suggested that global histone modifications are predictors of cancer recurrence in various tumor entities. Our study was performed to evaluate histone H3 lysine 4 mono-methyl (H3K4Me1), -di-methyl (H3K4me2) and -trimethyl (H3K4me3) patterns in renal cell carcinoma (RCC) using a tissue microarray with 193 RCC (including 142 clear cell, 31 papillary, 10 chromophobe and 10 sarcomatoid RCC) and 10 oncocytoma specimens: H3K4me3 staining was more intense in papillary RCC, whereas H3K4Me1 and H3K4me2 were similar in the diverse RCC subtypes. H3K4me2 and H3K4me3 levels were increased in oncocytoma. H3K4Me1-3 levels were inversely correlated with Fuhrman grading, pT stage, lymph node involvement and distant metastasis. Progression-free survival and cancer-specific survival were shorter in patients with low levels of H3K4Me1-3 in the univariate analysis, but we did not observe a significant correlation of a single modification in a multivariate model, which also included the established prognostic parameters TNM-stage and Fuhrman grade. In comparison, the H3K4me score, which combined staining levels of the H3K4 modifications, was an independent predictor of RCC progression-free survival. Our study on H3K4 methylation supports the concept of global histone modifications as potential cancer prognosis markers.

Benjamin A. Garcia - One of the best experts on this subject based on the ideXlab platform.

  • a specific lsd1 kdm1a isoform regulates neuronal differentiation through h3k9 demethylation
    Molecular Cell, 2015
    Co-Authors: Benoit Laurent, Lv Ruitu, Jernej Murn, Kristina Hempel, Ryan Ferrao, Yang Xiang, Shichong Liu, Benjamin A. Garcia
    Abstract:

    Lysine-specific demethylase 1 (LSD1) has been reported to repress and activate transcription by mediating histone H3K4Me1/2 and H3K9me1/2 demethylation, respectively. The molecular mechanism that underlies this dual substrate specificity has remained unknown. Here we report that an isoform of LSD1, LSD1+8a, does not have the intrinsic capability to demethylate H3K4me2. Instead, LSD1+8a mediates H3K9me2 demethylation in collaboration with supervillin (SVIL), a new LSD1+8a interacting protein. LSD1+8a knockdown increases H3K9me2, but not H3K4me2, levels at its target promoters and compromises neuronal differentiation. Importantly, SVIL co-localizes to LSD1+8a-bound promoters, and its knockdown mimics the impact of LSD1+8a loss, supporting SVIL as a cofactor for LSD1+8a in neuronal cells. These findings provide insight into mechanisms by which LSD1 mediates H3K9me demethylation and highlight alternative splicing as a means by which LSD1 acquires selective substrate specificities (H3K9 versus H3K4) to differentially control specific gene expression programs in neurons.

  • A Specific LSD1/KDM1A Isoform Regulates Neuronal Differentiation through H3K9 Demethylation
    Molecular cell, 2015
    Co-Authors: Benoit Laurent, Lv Ruitu, Jernej Murn, Kristina Hempel, Ryan Ferrao, Yang Xiang, Shichong Liu, Benjamin A. Garcia
    Abstract:

    Lysine-specific demethylase 1 (LSD1) has been reported to repress and activate transcription by mediating histone H3K4Me1/2 and H3K9me1/2 demethylation, respectively. The molecular mechanism that underlies this dual substrate specificity has remained unknown. Here we report that an isoform of LSD1, LSD1+8a, does not have the intrinsic capability to demethylate H3K4me2. Instead, LSD1+8a mediates H3K9me2 demethylation in collaboration with supervillin (SVIL), a new LSD1+8a interacting protein. LSD1+8a knockdown increases H3K9me2, but not H3K4me2, levels at its target promoters and compromises neuronal differentiation. Importantly, SVIL co-localizes to LSD1+8a-bound promoters, and its knockdown mimics the impact of LSD1+8a loss, supporting SVIL as a cofactor for LSD1+8a in neuronal cells. These findings provide insight into mechanisms by which LSD1 mediates H3K9me demethylation and highlight alternative splicing as a means by which LSD1 acquires selective substrate specificities (H3K9 versus H3K4) to differentially control specific gene expression programs in neurons.

Geraldine Delbes - One of the best experts on this subject based on the ideXlab platform.

  • Fetal testis organ culture reproduces the dynamics of epigenetic reprogramming in rat gonocytes
    Epigenetics & chromatin, 2017
    Co-Authors: Arlette Rwigemera, Fabien Joao, Geraldine Delbes
    Abstract:

    Epigenetic reprogramming is a critical step in male germ cell development that occurs during perinatal life. It is characterized by the remodeling of different epigenetic marks such as DNA methylation (5mC) and methylation of histone H3. It has been suggested that endocrine disruptors can affect the male germline epigenome by altering epigenetic reprogramming, but the mechanisms involved are still unknown. We have previously used an organ culture system that maintains the development of the different fetal testis cell types, to evaluate the effects of various endocrine disruptors on gametogenesis and steroidogenesis in the rat. We hypothesize that this culture model can reproduce the epigenetic reprogramming in gonocytes. Our aim was to establish the kinetics of three epigenetic marks throughout perinatal development in rats in vivo and compare them after different culture times. Using immunofluorescence, we showed that H3K4me2 transiently increased in gonocytes at 18.5 days post-coitum (dpc), while H3K4me3 displayed a stable increase in gonocytes from 18.5 dpc until after birth. 5mC progressively increased from 20.5 dpc until after birth. Using GFP-positive gonocytes purified from GCS-EGFP rats, we established the chronology of re-methylation of H19 and Snrpn in rat gonocytes. Most importantly, using testis explanted at 16.5 or 18.5 dpc and cultured for 2–4 days, we demonstrated that the kinetics of changes in H3K4me2, H3K4me3, global DNA methylation and on parental imprints can generally be reproduced ex vivo with the model of organ culture without the addition of serum. This study reveals the chronology of three epigenetic marks (H3K4me2, H3K4me3 and 5mC) and the patterns of methylation of H19 and Snrpn differentially methylated regions in rat gonocytes during perinatal development. Most importantly, our results suggest that the organ culture can reproduce the process of epigenetic reprogramming and can be used to study the impact of environmental chemicals on the establishment of the male germ cell epigenome.

  • Fetal testis organ culture reproduces the dynamics of epigenetic reprogramming in rat gonocytes
    Epigenetics & Chromatin, 2017
    Co-Authors: Arlette Rwigemera, Fabien Joao, Geraldine Delbes
    Abstract:

    Background Epigenetic reprogramming is a critical step in male germ cell development that occurs during perinatal life. It is characterized by the remodeling of different epigenetic marks such as DNA methylation (5mC) and methylation of histone H3. It has been suggested that endocrine disruptors can affect the male germline epigenome by altering epigenetic reprogramming, but the mechanisms involved are still unknown. We have previously used an organ culture system that maintains the development of the different fetal testis cell types, to evaluate the effects of various endocrine disruptors on gametogenesis and steroidogenesis in the rat. We hypothesize that this culture model can reproduce the epigenetic reprogramming in gonocytes. Our aim was to establish the kinetics of three epigenetic marks throughout perinatal development in rats in vivo and compare them after different culture times. Results Using immunofluorescence, we showed that H3K4me2 transiently increased in gonocytes at 18.5 days post-coitum (dpc), while H3K4me3 displayed a stable increase in gonocytes from 18.5 dpc until after birth. 5mC progressively increased from 20.5 dpc until after birth. Using GFP-positive gonocytes purified from GCS-EGFP rats, we established the chronology of re-methylation of H19 and Snrpn in rat gonocytes. Most importantly, using testis explanted at 16.5 or 18.5 dpc and cultured for 2–4 days, we demonstrated that the kinetics of changes in H3K4me2, H3K4me3, global DNA methylation and on parental imprints can generally be reproduced ex vivo with the model of organ culture without the addition of serum. Conclusions This study reveals the chronology of three epigenetic marks (H3K4me2, H3K4me3 and 5mC) and the patterns of methylation of H19 and Snrpn differentially methylated regions in rat gonocytes during perinatal development. Most importantly, our results suggest that the organ culture can reproduce the process of epigenetic reprogramming and can be used to study the impact of environmental chemicals on the establishment of the male germ cell epigenome.

Scott D Briggs - One of the best experts on this subject based on the ideXlab platform.

  • ccr4 not complex associates with the proteasome and regulates histone methylation
    Proceedings of the National Academy of Sciences of the United States of America, 2007
    Co-Authors: Nicholas R Laribee, Yoichiro Shibata, Douglas P Mersman, Sean R Collins, Patrick Kemmeren, Assen Roguev, Jonathan S Weissman, Scott D Briggs
    Abstract:

    The proteasome regulates histone lysine methylation and gene transcription, but how it does so is poorly understood. To better understand this process, we used the epistatic miniarray profile (E-MAP) approach to identify factors that genetically interact with proteasomal subunits. In addition to members of the Set1 complex that mediate histone H3 lysine 4 methylation (H3K4me), we found that deleting members of the CCR4/NOT mRNA processing complex exhibit synthetic phenotypes when combined with proteasome mutants. Further biochemical analyses revealed physical associations between CCR4/NOT and the proteasome in vivo. Consistent with the genetic and biochemical interactions linking CCR4/NOT with proteasome and Set1-mediated methylation, we find that loss of Not4 decreases global and gene-specific H3K4 trimethylation (H3K4me3) and decreases 19S proteasome recruitment to the PMA1 gene. Similar to proteasome regulation of histone methylation, loss of CCR4/NOT members does not affect ubiquitinated H2B. Mapping of Not4 identified the RING finger domain as essential for H3K4me3, suggesting a role for ubiquitin in this process. Consistent with this idea, loss of the Not4-interacting protein Ubc4, a known ubiquitin-conjugating enzyme, decreases H3K4me3. These studies implicate CCR4/NOT in the regulation of H3K4me3 through a ubiquitin-dependent pathway that likely involves the proteasome.

  • CCR4/NOT complex associates with the proteasome and regulates histone methylation
    Proceedings of the National Academy of Sciences of the United States of America, 2007
    Co-Authors: R. Nicholas Laribee, Yoichiro Shibata, Douglas P Mersman, Sean R Collins, Patrick Kemmeren, Assen Roguev, Jonathan S Weissman, Scott D Briggs, Nevan J. Krogan, Brian D. Strahl
    Abstract:

    The proteasome regulates histone lysine methylation and gene transcription, but how it does so is poorly understood. To better understand this process, we used the epistatic miniarray profile (E-MAP) approach to identify factors that genetically interact with proteasomal subunits. In addition to members of the Set1 complex that mediate histone H3 lysine 4 methylation (H3K4me), we found that deleting members of the CCR4/NOT mRNA processing complex exhibit synthetic phenotypes when combined with proteasome mutants. Further biochemical analyses revealed physical associations between CCR4/NOT and the proteasome in vivo. Consistent with the genetic and biochemical interactions linking CCR4/NOT with proteasome and Set1-mediated methylation, we find that loss of Not4 decreases global and gene-specific H3K4 trimethylation (H3K4me3) and decreases 19S proteasome recruitment to the PMA1 gene. Similar to proteasome regulation of histone methylation, loss of CCR4/NOT members does not affect ubiquitinated H2B. Mapping of Not4 identified the RING finger domain as essential for H3K4me3, suggesting a role for ubiquitin in this process. Consistent with this idea, loss of the Not4-interacting protein Ubc4, a known ubiquitin-conjugating enzyme, decreases H3K4me3. These studies implicate CCR4/NOT in the regulation of H3K4me3 through a ubiquitin-dependent pathway that likely involves the proteasome.

Jonathan S Weissman - One of the best experts on this subject based on the ideXlab platform.

  • ccr4 not complex associates with the proteasome and regulates histone methylation
    Proceedings of the National Academy of Sciences of the United States of America, 2007
    Co-Authors: Nicholas R Laribee, Yoichiro Shibata, Douglas P Mersman, Sean R Collins, Patrick Kemmeren, Assen Roguev, Jonathan S Weissman, Scott D Briggs
    Abstract:

    The proteasome regulates histone lysine methylation and gene transcription, but how it does so is poorly understood. To better understand this process, we used the epistatic miniarray profile (E-MAP) approach to identify factors that genetically interact with proteasomal subunits. In addition to members of the Set1 complex that mediate histone H3 lysine 4 methylation (H3K4me), we found that deleting members of the CCR4/NOT mRNA processing complex exhibit synthetic phenotypes when combined with proteasome mutants. Further biochemical analyses revealed physical associations between CCR4/NOT and the proteasome in vivo. Consistent with the genetic and biochemical interactions linking CCR4/NOT with proteasome and Set1-mediated methylation, we find that loss of Not4 decreases global and gene-specific H3K4 trimethylation (H3K4me3) and decreases 19S proteasome recruitment to the PMA1 gene. Similar to proteasome regulation of histone methylation, loss of CCR4/NOT members does not affect ubiquitinated H2B. Mapping of Not4 identified the RING finger domain as essential for H3K4me3, suggesting a role for ubiquitin in this process. Consistent with this idea, loss of the Not4-interacting protein Ubc4, a known ubiquitin-conjugating enzyme, decreases H3K4me3. These studies implicate CCR4/NOT in the regulation of H3K4me3 through a ubiquitin-dependent pathway that likely involves the proteasome.

  • CCR4/NOT complex associates with the proteasome and regulates histone methylation
    Proceedings of the National Academy of Sciences of the United States of America, 2007
    Co-Authors: R. Nicholas Laribee, Yoichiro Shibata, Douglas P Mersman, Sean R Collins, Patrick Kemmeren, Assen Roguev, Jonathan S Weissman, Scott D Briggs, Nevan J. Krogan, Brian D. Strahl
    Abstract:

    The proteasome regulates histone lysine methylation and gene transcription, but how it does so is poorly understood. To better understand this process, we used the epistatic miniarray profile (E-MAP) approach to identify factors that genetically interact with proteasomal subunits. In addition to members of the Set1 complex that mediate histone H3 lysine 4 methylation (H3K4me), we found that deleting members of the CCR4/NOT mRNA processing complex exhibit synthetic phenotypes when combined with proteasome mutants. Further biochemical analyses revealed physical associations between CCR4/NOT and the proteasome in vivo. Consistent with the genetic and biochemical interactions linking CCR4/NOT with proteasome and Set1-mediated methylation, we find that loss of Not4 decreases global and gene-specific H3K4 trimethylation (H3K4me3) and decreases 19S proteasome recruitment to the PMA1 gene. Similar to proteasome regulation of histone methylation, loss of CCR4/NOT members does not affect ubiquitinated H2B. Mapping of Not4 identified the RING finger domain as essential for H3K4me3, suggesting a role for ubiquitin in this process. Consistent with this idea, loss of the Not4-interacting protein Ubc4, a known ubiquitin-conjugating enzyme, decreases H3K4me3. These studies implicate CCR4/NOT in the regulation of H3K4me3 through a ubiquitin-dependent pathway that likely involves the proteasome.