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Monica P. Colaiácovo - One of the best experts on this subject based on the ideXlab platform.
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fanconi anemia fancm fncm 1 and fancd2 fcd 2 are required for maintaining Histone Methylation levels and interact with the Histone demethylase lsd1 spr 5 in caenorhabditis elegans
2018Co-Authors: Hyun-min Kim, Sara E Beesesims, Monica P. ColaiácovoAbstract:The Histone demethylase LSD1 was originally discovered by removing methyl groups from di- and monomethylated Histone H3 lysine 4 (H3K4me2/1). Several studies suggest that LSD1 plays roles in meiosis as well as in the epigenetic regulation of fertility given that, in its absence, there is evidence of a progressive accumulation of H3K4me2 and increased sterility through generations. In addition to the progressive sterility phenotype observed in the mutants, growing evidence for the importance of Histone Methylation in the regulation of DNA damage repair has attracted more attention to the field in recent years. However, we are still far from understanding the mechanisms by which Histone Methylation is involved in DNA damage repair, and only a few studies have focused on the roles of Histone demethylases in germline maintenance. Here, we show that the Histone demethylase LSD1/CeSPR-5 interacts with the Fanconi anemia (FA) protein FANCM/CeFNCM-1 using biochemical, cytological, and genetic analyses. LSD1/CeSPR-5 is required for replication stress-induced S phase-checkpoint activation, and its absence suppresses the embryonic lethality and larval arrest observed in fncm-1 mutants. FANCM/CeFNCM-1 relocalizes upon hydroxyurea exposure and colocalizes with FANCD2/CeFCD-2 and LSD1/CeSPR-5, suggesting coordination between this Histone demethylase and FA components to resolve replication stress. Surprisingly, the FA pathway is required for H3K4me2 maintenance, regardless of the presence of replication stress. Our study reveals a connection between FA and epigenetic maintenance and therefore provides new mechanistic insight into the regulation of Histone Methylation in DNA repair.
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fanconi anemia fancm fncm 1 and fancd2 fcd 2 are required for maintaining Histone Methylation levels and interact with the Histone demethylase lsd1 spr 5 in c elegans
2018Co-Authors: Hyun-min Kim, Sara E Beesesims, Monica P. ColaiácovoAbstract:The Histone demethylase LSD1 was originally discovered as removing methyl groups from di- and monomethylated Histone H3 lysine 4 (H3K4me2/1), and several studies suggest it plays roles in meiosis as well as epigenetic sterility given that in its absence there is evidence of a progressive accumulation of H3K4me2 through generations. In addition to transgenerational sterility, growing evidence for the importance of Histone Methylation in the regulation of DNA damage repair has attracted more attention to the field in recent years. However, we are still far from understanding the mechanisms by which Histone Methylation is involved in DNA damage repair and only a few studies have been focused on the roles of Histone demethylases in germline maintenance. Here, we show that the Histone demethylase LSD1/CeSPR-5 is interacting with the Fanconi Anemia (FA) protein FANCM/CeFNCM-1 based on biochemical, cytological and genetic analyses. LSD1/CeSPR-5 is required for replication stress-induced S-phase checkpoint activation and its absence suppresses the embryonic lethality and larval arrest observed in fncm-1 mutants. FANCM/CeFNCM-1 re-localizes upon hydroxyurea exposure and co-localizes with FANCD2/CeFCD-2 and LSD1/CeSPR-5 suggesting coordination between this Histone demethylase and FA components to resolve replication stress. Surprisingly, the FA pathway is required for H3K4me2 maintenance regardless of the presence of replication stress. Our study reveals a connection between Fanconi Anemia and epigenetic maintenance, therefore providing new mechanistic insight into the regulation of Histone Methylation in DNA repair.
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reversal of Histone lysine triMethylation by the jmjd2 family of Histone demethylases
2006Co-Authors: Johnatha R Whetstine, Monica P. Colaiácovo, Amanda C Nottke, Maite Huarte, Sari Smolikov, Zhongzhou Che, Eric Spoone, Gongyi Zhang, Yang ShiAbstract:Histone Methylation regulates chromatin structure, transcription, and epigenetic state of the cell. Histone Methylation is dynamically regulated by Histone methylases and demethylases such as LSD1 and JHDM1, which mediate deMethylation of di- and monomethylated Histones. It has been unclear whether demethylases exist that reverse lysine triMethylation. We show the JmjC domain-containing protein JMJD2A reversed trimethylated H3-K9/K36 to di- but not mono- or unmethylated products. Overexpression of JMJD2A but not a catalytically inactive mutant reduced H3-K9/K36 triMethylation levels in cultured cells. In contrast, RNAi depletion of the C. elegans JMJD2A homolog resulted in an increase in general H3-K9Me3 and localized H3-K36Me3 levels on meiotic chromosomes and triggered p53-dependent germline apoptosis. Additionally, other human JMJD2 subfamily members also functioned as triMethylation-specific demethylases, converting H3-K9Me3 to H3-K9Me2 and H3-K9Me1, respectively. Our finding that this family of demethylases generates different methylated states at the same lysine residue provides a mechanism for fine-tuning Histone Methylation.
Tony Kouzarides - One of the best experts on this subject based on the ideXlab platform.
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nucleosome interacting proteins regulated by dna and Histone Methylation
2010Co-Authors: Till Bartke, Michiel Vermeulen, Blerta Xhemalce, Samuel Robson, Matthias Mann, Tony KouzaridesAbstract:Summary Modifications on Histones or on DNA recruit proteins that regulate chromatin function. Here, we use nucleosomes methylated on DNA and on Histone H3 in an affinity assay, in conjunction with a SILAC-based proteomic analysis, to identify "crosstalk" between these two distinct classes of modification. Our analysis reveals proteins whose binding to nucleosomes is regulated by Methylation of CpGs, H3K4, H3K9, and H3K27 or a combination thereof. We identify the origin recognition complex (ORC), including LRWD1 as a subunit, to be a Methylation-sensitive nucleosome interactor that is recruited cooperatively by DNA and Histone Methylation. Other interactors, such as the lysine demethylase Fbxl11/KDM2A, recognize nucleosomes methylated on Histones, but their recruitment is disrupted by DNA Methylation. These data establish SILAC nucleosome affinity purifications (SNAP) as a tool for studying the dynamics between different chromatin modifications and provide a modification binding "profile" for proteins regulated by DNA and Histone Methylation.
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Reversing Histone Methylation
2005Co-Authors: Andrew J. Bannister, Tony KouzaridesAbstract:Histones package DNA, and post-translational modifications of Histones can regulate access to DNA. Until recently, Histone Methylation-unlike all other Histone modifications-was considered a permanent mark. The discovery of enzymes that reverse the Methylation of lysines and arginines challenges our current thinking on the unique nature of Histone Methylation, and substantially increases the complexity of Histone modification pathways.
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the methyl cpg binding protein mecp2 links dna Methylation to Histone Methylation
2003Co-Authors: Francois Fuks, Paul J Hurd, Daniel Wolf, Adrian Bird, Tony KouzaridesAbstract:Abstract DNA Methylation plays an important role in mammalian development and correlates with chromatin-associated gene silencing. The recruitment of MeCP2 to methylated CpG dinucleotides represents a major mechanism by which DNA Methylation can repress transcription. MeCP2 silences gene expression partly by recruiting Histone deacetylase (HDAC) activity, resulting in chromatin remodeling. Here, we show that MeCP2 associates with Histone methyltransferase activity in vivo and that this activity is directed against Lys9 of Histone H3. Two characterized repression domains of MeCP2 are involved in tethering the Histone methyltransferase to MeCP2. We asked if MeCP2 can deliver Lys9 H3 Methylation to the H19 gene, whose activity it represses. We show that the presence of MeCP2 on nucleosomes within the repressor region of the H19 gene (the differentially methylated domain) coincides with an increase in H3 Lys9Methylation. Our data provide evidence that MeCP2 reinforces a repressive chromatin state by acting as a bridge between two global epigenetic modifications, DNA Methylation and Histone Methylation.
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Histone Methylation dynamic or static
2002Co-Authors: Andrew J. Bannister, Robert Schneider, Tony KouzaridesAbstract:Methylation of Histones mediates transcriptional silencing at heterochromatin sites and affects regulated transcription at euchromatic loci. So is the methyl group a permanent mark on Histones, or can it be removed by an active process necessary for regulated gene expression?
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Histone Methylation in transcriptional control
2002Co-Authors: Tony KouzaridesAbstract:Abstract Over the past year or so, Methylation of Histones has come to be recognised as a major player in the regulation of gene activity. This notion follows the discovery of lysine and arginine methyltransferases and proteins that recognise the methyl-lysine ‘mark’ on Histones. Methylated Histones have been implicated in heterochromatic repression, promoter regulation and the propagation of a repressed state via DNA Methylation.
Hyun-min Kim - One of the best experts on this subject based on the ideXlab platform.
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fanconi anemia fancm fncm 1 and fancd2 fcd 2 are required for maintaining Histone Methylation levels and interact with the Histone demethylase lsd1 spr 5 in caenorhabditis elegans
2018Co-Authors: Hyun-min Kim, Sara E Beesesims, Monica P. ColaiácovoAbstract:The Histone demethylase LSD1 was originally discovered by removing methyl groups from di- and monomethylated Histone H3 lysine 4 (H3K4me2/1). Several studies suggest that LSD1 plays roles in meiosis as well as in the epigenetic regulation of fertility given that, in its absence, there is evidence of a progressive accumulation of H3K4me2 and increased sterility through generations. In addition to the progressive sterility phenotype observed in the mutants, growing evidence for the importance of Histone Methylation in the regulation of DNA damage repair has attracted more attention to the field in recent years. However, we are still far from understanding the mechanisms by which Histone Methylation is involved in DNA damage repair, and only a few studies have focused on the roles of Histone demethylases in germline maintenance. Here, we show that the Histone demethylase LSD1/CeSPR-5 interacts with the Fanconi anemia (FA) protein FANCM/CeFNCM-1 using biochemical, cytological, and genetic analyses. LSD1/CeSPR-5 is required for replication stress-induced S phase-checkpoint activation, and its absence suppresses the embryonic lethality and larval arrest observed in fncm-1 mutants. FANCM/CeFNCM-1 relocalizes upon hydroxyurea exposure and colocalizes with FANCD2/CeFCD-2 and LSD1/CeSPR-5, suggesting coordination between this Histone demethylase and FA components to resolve replication stress. Surprisingly, the FA pathway is required for H3K4me2 maintenance, regardless of the presence of replication stress. Our study reveals a connection between FA and epigenetic maintenance and therefore provides new mechanistic insight into the regulation of Histone Methylation in DNA repair.
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fanconi anemia fancm fncm 1 and fancd2 fcd 2 are required for maintaining Histone Methylation levels and interact with the Histone demethylase lsd1 spr 5 in c elegans
2018Co-Authors: Hyun-min Kim, Sara E Beesesims, Monica P. ColaiácovoAbstract:The Histone demethylase LSD1 was originally discovered as removing methyl groups from di- and monomethylated Histone H3 lysine 4 (H3K4me2/1), and several studies suggest it plays roles in meiosis as well as epigenetic sterility given that in its absence there is evidence of a progressive accumulation of H3K4me2 through generations. In addition to transgenerational sterility, growing evidence for the importance of Histone Methylation in the regulation of DNA damage repair has attracted more attention to the field in recent years. However, we are still far from understanding the mechanisms by which Histone Methylation is involved in DNA damage repair and only a few studies have been focused on the roles of Histone demethylases in germline maintenance. Here, we show that the Histone demethylase LSD1/CeSPR-5 is interacting with the Fanconi Anemia (FA) protein FANCM/CeFNCM-1 based on biochemical, cytological and genetic analyses. LSD1/CeSPR-5 is required for replication stress-induced S-phase checkpoint activation and its absence suppresses the embryonic lethality and larval arrest observed in fncm-1 mutants. FANCM/CeFNCM-1 re-localizes upon hydroxyurea exposure and co-localizes with FANCD2/CeFCD-2 and LSD1/CeSPR-5 suggesting coordination between this Histone demethylase and FA components to resolve replication stress. Surprisingly, the FA pathway is required for H3K4me2 maintenance regardless of the presence of replication stress. Our study reveals a connection between Fanconi Anemia and epigenetic maintenance, therefore providing new mechanistic insight into the regulation of Histone Methylation in DNA repair.
Yi Zhang - One of the best experts on this subject based on the ideXlab platform.
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plu 1 is an h3k4 demethylase involved in transcriptional repression and breast cancer cell proliferation
2007Co-Authors: Kenichi Yamane, Robert J Klose, Keisuke Tateishi, Jia Fang, Laura A Fabrizio, Hediye Erdjumentbromage, Joyce Taylorpapadimitriou, Paul Tempst, Yi ZhangAbstract:Posttranslational modification of chromatin by Histone Methylation has wide-ranging effects on nuclear function, including transcriptional regulation, maintenance of genome integrity, and epigenetic inheritance. The enzymes utilized to place Histone Methylation marks are well characterized, but the identity of a Histone deMethylation system remained elusive until recently. The discovery of Histone demethylase enzymes capable of directly removing methyl groups from modified lysine residues has demonstrated that Histone Methylation is a dynamic modification. The most extensive family of Histone demethylase enzymes identified so far contains a JmjC domain and catalyzes deMethylation through a hydroxylation reaction. Here, we identify PLU-1, a transcriptional repressor implicated in breast cancer, as a Histone demethylase enzyme that has the ability to reverse the trimethyl H3K4 modification state. Furthermore, we reveal that PLU-1-mediated H3K4 demethylase activity plays an important role in the proliferative capacity of breast cancer cells through repression of tumor suppressor genes, including BRCA1.
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the retinoblastoma binding protein rbp2 is an h3k4 demethylase
2007Co-Authors: Robert J Klose, Yi Zhang, Kenichi Yamane, Hediye Erdjumentbromage, Paul Tempst, Zuzana Tothova, Gary D Gilliland, William G KaelinAbstract:Summary Changes in Histone Methylation status regulate chromatin structure and DNA-dependent processes such as transcription. Recent studies indicate that, analogous to other Histone modifications, Histone Methylation is reversible. Retinoblastoma binding protein 2 (RBP2), a nuclear protein implicated in the regulation of transcription and differentiation by the retinoblastoma tumor suppressor protein, contains a JmjC domain recently defined as a Histone demethylase signature motif. Here we report that RBP2 is a demethylase that specifically catalyzes deMethylation on H3K4, whose Methylation is normally associated with transcriptionally active genes. RBP2 −/− mouse cells displayed enhanced transcription of certain cytokine genes, which, in the case of SDF1 , was associated with increased H3K4 triMethylation. Furthermore, RBP2 specifically demethylated H3K4 in biochemical and cell-based assays. These studies provide mechanistic insights into transcriptional regulation by RBP2 and provide the first example of a mammalian enzyme capable of erasing trimethylated H3K4.
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regulation of Histone Methylation by demethylimination and deMethylation
2007Co-Authors: Robert J Klose, Yi ZhangAbstract:Methylation of Histone residues is important for the regulation of gene transcription, epigenetic inheritance and cell fate. Histone Methylation was long considered a stable modification, but the recent identification of a Histone deiminase and Histone demethylases has shown that Histone Methylation can be dynamically regulated. Histone Methylation has important roles in regulating transcription, genome integrity and epigenetic inheritance. Historically, methylated Histone arginine and lysine residues have been considered static modifications because of the low levels of methyl-group turnover in chromatin. The recent identification of enzymes that antagonize or remove Histone Methylation has changed this view and now the dynamic nature of these modifications is being appreciated. Here, we examine the enzymatic and structural basis for the mechanisms that these enzymes use to counteract Histone Methylation and provide insights into their substrate specificity and biological function.
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regulation of Histone Methylation by demethylimination and deMethylation
2007Co-Authors: Robert J Klose, Yi ZhangAbstract:Histone Methylation has important roles in regulating transcription, genome integrity and epigenetic inheritance. Historically, methylated Histone arginine and lysine residues have been considered static modifications because of the low levels of methyl-group turnover in chromatin. The recent identification of enzymes that antagonize or remove Histone Methylation has changed this view and now the dynamic nature of these modifications is being appreciated. Here, we examine the enzymatic and structural basis for the mechanisms that these enzymes use to counteract Histone Methylation and provide insights into their substrate specificity and biological function.
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hDOT1L Links Histone Methylation to Leukemogenesis
2005Co-Authors: Yuki Okada, Qin Feng, Yihui Lin, Qi Jiang, Vernon M. Coffield, Yi ZhangAbstract:Epigenetic modifications play an important role in human cancer. One such modification, Histone Methylation, contributes to human cancer through deregulation of cancer-relevant genes. The yeast Dot1 and its human counterpart, hDOT1L, methylate lysine 79 located within the globular domain of Histone H3. Here we report that hDOT1L interacts with AF10, an MLL (mixed lineage leukemia) fusion partner involved in acute myeloid leukemia, through the OM-LZ region of AF10 required for MLL-AF10-mediated leukemogenesis. We demonstrate that direct fusion of hDOT1L to MLL results in leukemic transformation in an hDOT1L methyltransferase activity-dependent manner. Transformation by MLL-hDOT1L and MLL-AF10 results in upregulation of a number of leukemia-relevant genes, such as Hoxa9, concomitant with hyperMethylation of H3-K79. Our studies thus establish that mistargeting of hDOT1L to Hoxa9 plays an important role in MLL-AF10-mediated leukemogenesis and suggests that the enzymatic activity of hDOT1L may provide a potential target for therapeutic intervention.
Yang Shi - One of the best experts on this subject based on the ideXlab platform.
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Histone Methylation: A dynamic mark in health, disease and inheritance
2012Co-Authors: Eric L Greer, Yang ShiAbstract:Organisms require an appropriate balance of stability and reversibility in gene expression programmes to maintain cell identity or to enable responses to stimuli; epigenetic regulation is integral to this dynamic control. Post-translational modification of Histones by Methylation is an important and widespread type of chromatin modification that is known to influence biological processes in the context of development and cellular responses. To evaluate how Histone Methylation contributes to stable or reversible control, we provide a broad overview of how Histone Methylation is regulated and leads to biological outcomes. The importance of appropriately maintaining or reprogramming Histone Methylation is illustrated by its links to disease and ageing and possibly to transmission of traits across generations.
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reversal of Histone Methylation biochemical and molecular mechanisms of Histone demethylases
2010Co-Authors: Nima Mosammaparast, Yang ShiAbstract:The importance of Histone Methylation in gene regulation was suggested over 40 years ago. Yet, the dynamic nature of this Histone modification was recognized only recently, with the discovery of the first Histone demethylase nearly five years ago. Since then, our insight into the mechanisms, structures, and macromolecular complexes of these enzymes has grown exponentially. Overall, the evidence strongly supports a key role for Histone demethylases in eukaryotic transcription and other chromatin-dependent processes. Here, we examine these and related facets of Histone demethylases discovered to date, focusing on their biochemistry, structure, and enzymology.
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reversal of Histone lysine triMethylation by the jmjd2 family of Histone demethylases
2006Co-Authors: Johnatha R Whetstine, Monica P. Colaiácovo, Amanda C Nottke, Maite Huarte, Sari Smolikov, Zhongzhou Che, Eric Spoone, Gongyi Zhang, Yang ShiAbstract:Histone Methylation regulates chromatin structure, transcription, and epigenetic state of the cell. Histone Methylation is dynamically regulated by Histone methylases and demethylases such as LSD1 and JHDM1, which mediate deMethylation of di- and monomethylated Histones. It has been unclear whether demethylases exist that reverse lysine triMethylation. We show the JmjC domain-containing protein JMJD2A reversed trimethylated H3-K9/K36 to di- but not mono- or unmethylated products. Overexpression of JMJD2A but not a catalytically inactive mutant reduced H3-K9/K36 triMethylation levels in cultured cells. In contrast, RNAi depletion of the C. elegans JMJD2A homolog resulted in an increase in general H3-K9Me3 and localized H3-K36Me3 levels on meiotic chromosomes and triggered p53-dependent germline apoptosis. Additionally, other human JMJD2 subfamily members also functioned as triMethylation-specific demethylases, converting H3-K9Me3 to H3-K9Me2 and H3-K9Me1, respectively. Our finding that this family of demethylases generates different methylated states at the same lysine residue provides a mechanism for fine-tuning Histone Methylation.