Histone Methyltransferase MMSET/NSD2 Alters EZH2 Binding and Reprograms the Myeloma Epigenome through Global and Focal Changes in H3K36 and H3K27 Methylation
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{"title"=>"Histone Methyltransferase MMSET/NSD2 Alters EZH2 Binding and Reprograms the Myeloma Epigenome through Global and Focal Changes in H3K36 and H3K27 Methylation", "type"=>"journal", "authors"=>[{"first_name"=>"Relja", "last_name"=>"Popovic", "scopus_author_id"=>"8846769600"}, {"first_name"=>"Eva", "last_name"=>"Martinez-Garcia", "scopus_author_id"=>"36843415400"}, {"first_name"=>"Eugenia G.", "last_name"=>"Giannopoulou", "scopus_author_id"=>"22834138200"}, {"first_name"=>"Quanwei", "last_name"=>"Zhang", "scopus_author_id"=>"55901442200"}, {"first_name"=>"Qingyang", "last_name"=>"Zhang", "scopus_author_id"=>"56192921500"}, {"first_name"=>"Teresa", "last_name"=>"Ezponda", "scopus_author_id"=>"16063013500"}, {"first_name"=>"Mrinal Y.", "last_name"=>"Shah", "scopus_author_id"=>"36464163100"}, {"first_name"=>"Yupeng", "last_name"=>"Zheng", "scopus_author_id"=>"36982699400"}, {"first_name"=>"Christine M.", "last_name"=>"Will", "scopus_author_id"=>"37038829700"}, {"first_name"=>"Eliza C.", "last_name"=>"Small", "scopus_author_id"=>"56208618600"}, {"first_name"=>"Youjia", "last_name"=>"Hua", "scopus_author_id"=>"56375232800"}, {"first_name"=>"Marinka", "last_name"=>"Bulic", "scopus_author_id"=>"35081786700"}, {"first_name"=>"Yanwen", "last_name"=>"Jiang", "scopus_author_id"=>"55584434900"}, {"first_name"=>"Matteo", "last_name"=>"Carrara", "scopus_author_id"=>"55308522500"}, {"first_name"=>"Raffaele A.", "last_name"=>"Calogero", "scopus_author_id"=>"7004035394"}, {"first_name"=>"William L.", "last_name"=>"Kath", "scopus_author_id"=>"7005904430"}, {"first_name"=>"Neil L.", "last_name"=>"Kelleher", "scopus_author_id"=>"7004106273"}, {"first_name"=>"Ji Ping", "last_name"=>"Wang", "scopus_author_id"=>"15835948900"}, {"first_name"=>"Olivier", "last_name"=>"Elemento", "scopus_author_id"=>"12779628700"}, {"first_name"=>"Jonathan D.", "last_name"=>"Licht", "scopus_author_id"=>"7004409924"}], "year"=>2014, "source"=>"PLoS Genetics", "identifiers"=>{"issn"=>"15537404", "scopus"=>"2-s2.0-84907572364", "pui"=>"600082256", "doi"=>"10.1371/journal.pgen.1004566", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)", "sgr"=>"84907572364", "pmid"=>"25188243"}, "id"=>"28109a1c-541a-322d-973c-bf8148629f29", "abstract"=>"Overexpression of the histone methyltransferase MMSET in t(4;14)+ multiple myeloma patients is believed to be the driving factor in the pathogenesis of this subtype of myeloma. MMSET catalyzes dimethylation of lysine 36 on histone H3 (H3K36me2), and its overexpression causes a global increase in H3K36me2, redistributing this mark in a broad, elevated level across the genome. Here, we demonstrate that an increased level of MMSET also induces a global reduction of lysine 27 trimethylation on histone H3 (H3K27me3). Despite the net decrease in H3K27 methylation, specific genomic loci exhibit enhanced recruitment of the EZH2 histone methyltransferase and become hypermethylated on this residue. These effects likely contribute to the myeloma phenotype since MMSET-overexpressing cells displayed increased sensitivity to EZH2 inhibition. Furthermore, we demonstrate that such MMSET-mediated epigenetic changes require a number of functional domains within the protein, including PHD domains that mediate MMSET recruitment to chromatin. In vivo, targeting of MMSET by an inducible shRNA reversed histone methylation changes and led to regression of established tumors in athymic mice. Together, our work elucidates previously unrecognized interplay between MMSET and EZH2 in myeloma oncogenesis and identifies domains to be considered when designing inhibitors of MMSET function.", "link"=>"http://www.mendeley.com/research/histone-methyltransferase-mmsetnsd2-alters-ezh2-binding-reprograms-myeloma-epigenome-through-global", "reader_count"=>104, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>8, "Researcher"=>34, "Student > Doctoral Student"=>7, "Student > Ph. D. Student"=>23, "Student > Postgraduate"=>2, "Student > Master"=>5, "Other"=>6, "Student > Bachelor"=>10, "Lecturer > Senior Lecturer"=>1, "Professor"=>5}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>8, "Researcher"=>34, "Student > Doctoral Student"=>7, "Student > Ph. D. Student"=>23, "Student > Postgraduate"=>2, "Student > Master"=>5, "Other"=>6, "Student > Bachelor"=>10, "Lecturer > Senior Lecturer"=>1, "Professor"=>5}, "reader_count_by_subject_area"=>{"Unspecified"=>8, "Biochemistry, Genetics and Molecular Biology"=>22, "Mathematics"=>1, "Agricultural and Biological Sciences"=>57, "Medicine and Dentistry"=>9, "Neuroscience"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Chemistry"=>2, "Computer Science"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>9}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>57}, "Computer Science"=>{"Computer Science"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>22}, "Mathematics"=>{"Mathematics"=>1}, "Unspecified"=>{"Unspecified"=>8}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}}, "reader_count_by_country"=>{"Austria"=>1, "Sweden"=>1, "United States"=>4, "Denmark"=>2, "United Kingdom"=>3, "Germany"=>1}, "group_count"=>2}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1663083"], "description"=>"<p>(A) Diagram of the MMSET constructs used. PHD2-M2 and PHD1-M2 constructs start at amino acid 712 and 657, respectively. Mutations in the PHD domains are indicated as stars above the full-length MMSET. (B) Representative immunoblot on nuclear extracts from repleted TKO cells probed with the indicated antibodies. At least two independent infections were performed for each construct. (C) Nuclear extracts from the TKO cells repleted with PHD mutants were immunoblotted with the indicated antibodies. At least two independent infections were performed for each construct. (D) Colony formation with TKO cells repleted with mutated PHD constructs. Experiment was performed in triplicate and at least six different fields were counted. Graph represents average colony count +/− standard deviation. (E) Quantitative RT-PCR of MMSET target genes <i>CR2</i> and <i>JAM3</i> using RNA from repleted TKO cells. Experiment was performed in duplicate and graph represents average gene expression +/− standard deviation. (F) Mutations in the PHD fingers prevent MMSET binding to chromatin. ChIP assay on the <i>JAM2</i> promoter using repleted TKO cells. Two independent biological replicates are shown.</p>", "links"=>[], "tags"=>["phd", "H 3K methylation", "genomic loci exhibit", "H 3K Methylation Overexpression", "lysine 27 trimethylation", "EZH 2 histone methyltransferase", "H 3K", "MMSET catalyzes dimethylation", "histone methylation changes", "histone methyltransferase MMSET", "EZH 2 inhibition", "myeloma", "histone H 3"], "article_id"=>1162427, "categories"=>["Uncategorised"], "users"=>["Relja Popovic", "Eva Martinez-Garcia", "Eugenia G. Giannopoulou", "Quanwei Zhang", "Qingyang Zhang", "Teresa Ezponda", "Mrinal Y. Shah", "Yupeng Zheng", "Christine M. Will", "Eliza C. Small", "Youjia Hua", "Marinka Bulic", "Yanwen Jiang", "Matteo Carrara", "Raffaele A. Calogero", "William L. Kath", "Neil L. Kelleher", "Ji-Ping Wang", "Olivier Elemento", "Jonathan D. Licht"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004566.g006", "stats"=>{"downloads"=>1, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PHD_fingers_2_and_3_are_required_for_proper_MMSET_function_/1162427", "title"=>"PHD fingers 2 and 3 are required for proper MMSET function.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-04 04:53:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/1663082"], "description"=>"<p>(A) Diagram of the wild-type (amino acids 1–1365) and deletion MMSET constructs used for repletion experiments. Star represents location of the Y1118A mutation. –PHD construct encompasses amino acids 1–1209 and –PWWP2 construct is missing amino acids 877–995. (B) Representative immunoblot of nuclear extracts from repleted TKO cells was probed with the indicated antibodies. At least two independent infections were performed for each construct. (C) Representative qRT-PCR for <i>JAM2</i> in repleted TKO cells. Measurements were performed from multiple infections in at least duplicate and the graph represents average expression +/− standard deviation. (D) Methylcellulose colony formation assay using repleted TKO cells. Experiment was performed in triplicate and at least six different fields were counted. Graph represents average colony count +/− standard deviation. (E) ChIP assay on the <i>JAM2</i> promoter using repleted TKO cell. Two independent biological replicates are shown.</p>", "links"=>[], "tags"=>["phd", "H 3K methylation", "genomic loci exhibit", "H 3K Methylation Overexpression", "lysine 27 trimethylation", "EZH 2 histone methyltransferase", "H 3K", "MMSET catalyzes dimethylation", "histone methylation changes", "histone methyltransferase MMSET", "EZH 2 inhibition", "myeloma", "histone H 3"], "article_id"=>1162426, "categories"=>["Uncategorised"], "users"=>["Relja Popovic", "Eva Martinez-Garcia", "Eugenia G. Giannopoulou", "Quanwei Zhang", "Qingyang Zhang", "Teresa Ezponda", "Mrinal Y. Shah", "Yupeng Zheng", "Christine M. Will", "Eliza C. Small", "Youjia Hua", "Marinka Bulic", "Yanwen Jiang", "Matteo Carrara", "Raffaele A. Calogero", "William L. Kath", "Neil L. Kelleher", "Ji-Ping Wang", "Olivier Elemento", "Jonathan D. Licht"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004566.g005", "stats"=>{"downloads"=>2, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_MMSET_induced_epigenetic_switch_depends_on_multiple_domains_/1162426", "title"=>"The MMSET-induced epigenetic switch depends on multiple domains.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-04 04:53:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/1663085", "https://ndownloader.figshare.com/files/1663086", "https://ndownloader.figshare.com/files/1663087", "https://ndownloader.figshare.com/files/1663088", "https://ndownloader.figshare.com/files/1663089", "https://ndownloader.figshare.com/files/1663090", "https://ndownloader.figshare.com/files/1663091", "https://ndownloader.figshare.com/files/1663092", "https://ndownloader.figshare.com/files/1663093", "https://ndownloader.figshare.com/files/1663094", "https://ndownloader.figshare.com/files/1663095", "https://ndownloader.figshare.com/files/1663096", "https://ndownloader.figshare.com/files/1663097", "https://ndownloader.figshare.com/files/1663098", "https://ndownloader.figshare.com/files/1663099", "https://ndownloader.figshare.com/files/1663100", "https://ndownloader.figshare.com/files/1663101"], "description"=>"<div><p>Overexpression of the histone methyltransferase MMSET in t(4;14)+ multiple myeloma patients is believed to be the driving factor in the pathogenesis of this subtype of myeloma. MMSET catalyzes dimethylation of lysine 36 on histone H3 (H3K36me2), and its overexpression causes a global increase in H3K36me2, redistributing this mark in a broad, elevated level across the genome. Here, we demonstrate that an increased level of MMSET also induces a global reduction of lysine 27 trimethylation on histone H3 (H3K27me3). Despite the net decrease in H3K27 methylation, specific genomic loci exhibit enhanced recruitment of the EZH2 histone methyltransferase and become hypermethylated on this residue. These effects likely contribute to the myeloma phenotype since MMSET-overexpressing cells displayed increased sensitivity to EZH2 inhibition. Furthermore, we demonstrate that such MMSET-mediated epigenetic changes require a number of functional domains within the protein, including PHD domains that mediate MMSET recruitment to chromatin. In vivo, targeting of <i>MMSET</i> by an inducible shRNA reversed histone methylation changes and led to regression of established tumors in athymic mice. Together, our work elucidates previously unrecognized interplay between MMSET and EZH2 in myeloma oncogenesis and identifies domains to be considered when designing inhibitors of MMSET function.</p></div>", "links"=>[], "tags"=>["phd", "H 3K methylation", "genomic loci exhibit", "H 3K Methylation Overexpression", "lysine 27 trimethylation", "EZH 2 histone methyltransferase", "H 3K", "MMSET catalyzes dimethylation", "histone methylation changes", "histone methyltransferase MMSET", "EZH 2 inhibition", "myeloma", "histone H 3"], "article_id"=>1162429, "categories"=>["Uncategorised"], "users"=>["Relja Popovic", "Eva Martinez-Garcia", "Eugenia G. Giannopoulou", "Quanwei Zhang", "Qingyang Zhang", "Teresa Ezponda", "Mrinal Y. Shah", "Yupeng Zheng", "Christine M. Will", "Erna Magnúsdóttir", "Eliza C. Small", "Youjia Hua", "Marinka Bulic", "Yanwen Jiang", "Matteo Carrara", "Raffaele A. Calogero", "William L. Kath", "Neil L. Kelleher", "Ji-Ping Wang", "Olivier Elemento", "Jonathan D. Licht"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004566.s001", "https://dx.doi.org/10.1371/journal.pgen.1004566.s002", "https://dx.doi.org/10.1371/journal.pgen.1004566.s003", "https://dx.doi.org/10.1371/journal.pgen.1004566.s004", "https://dx.doi.org/10.1371/journal.pgen.1004566.s005", "https://dx.doi.org/10.1371/journal.pgen.1004566.s006", "https://dx.doi.org/10.1371/journal.pgen.1004566.s007", "https://dx.doi.org/10.1371/journal.pgen.1004566.s008", "https://dx.doi.org/10.1371/journal.pgen.1004566.s009", "https://dx.doi.org/10.1371/journal.pgen.1004566.s010", "https://dx.doi.org/10.1371/journal.pgen.1004566.s011", "https://dx.doi.org/10.1371/journal.pgen.1004566.s012", "https://dx.doi.org/10.1371/journal.pgen.1004566.s013", "https://dx.doi.org/10.1371/journal.pgen.1004566.s014", "https://dx.doi.org/10.1371/journal.pgen.1004566.s015", "https://dx.doi.org/10.1371/journal.pgen.1004566.s016", "https://dx.doi.org/10.1371/journal.pgen.1004566.s017"], "stats"=>{"downloads"=>65, "page_views"=>41, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Histone_Methyltransferase_MMSET_NSD2_Alters_EZH2_Binding_and_Reprograms_the_Myeloma_Epigenome_through_Global_and_Focal_Changes_in_H3K36_and_H3K27_Methylation_/1162429", "title"=>"Histone Methyltransferase MMSET/NSD2 Alters EZH2 Binding and Reprograms the Myeloma Epigenome through Global and Focal Changes in H3K36 and H3K27 Methylation", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-09-04 04:53:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/1663084"], "description"=>"<p>(A) Mouse xenograft model using t(4;14)+ KMS11 cells harboring a luciferase gene and a doxycycline-inducible MMSET-specific shRNA. Animals that were not administered doxycycline (−Dox) are shown on the top and animals that were given doxycycline are shown on the bottom (+Dox). Two representative animals are shown from each group (n = 5) at the following timepoints: 2 weeks after treatment; 4 weeks after treatment; 2 weeks after release from Dox; and 4 weeks after release from Dox. –Dox animals were sacrificed 26 days after treatment initiation due to tumor size. The same two animals are shown at each time points. (B) Kaplan-Meier curve of the xenograft mouse experiment from A. (C) Measurement of the luciferin signal in treated (black) and untreated (red) mice over time. (D) Immunoblot for H3K36me2 and H3K27me3 using nuclear extracts from tumors isolated from the untreated or doxycycline-treated mice (E) Proposed model for explaining how MMSET overexpression alters the epigenetic landscape of myeloma cells. Methylation of H3K36 by MMSET induces a global decrease of H3K27me3, leading to activation of gene expression (bottom). Additionally, an overabundance of K36 methylation alters genome-wide EZH2 binding, inducing focal increases in H3K27 methylation and gene repression.</p>", "links"=>[], "tags"=>["phd", "H 3K methylation", "genomic loci exhibit", "H 3K Methylation Overexpression", "lysine 27 trimethylation", "EZH 2 histone methyltransferase", "H 3K", "MMSET catalyzes dimethylation", "histone methylation changes", "histone methyltransferase MMSET", "EZH 2 inhibition", "myeloma", "histone H 3"], "article_id"=>1162428, "categories"=>["Uncategorised"], "users"=>["Relja Popovic", "Eva Martinez-Garcia", "Eugenia G. Giannopoulou", "Quanwei Zhang", "Qingyang Zhang", "Teresa Ezponda", "Mrinal Y. Shah", "Yupeng Zheng", "Christine M. Will", "Eliza C. Small", "Youjia Hua", "Marinka Bulic", "Yanwen Jiang", "Matteo Carrara", "Raffaele A. Calogero", "William L. Kath", "Neil L. Kelleher", "Ji-Ping Wang", "Olivier Elemento", "Jonathan D. Licht"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004566.g007", "stats"=>{"downloads"=>6, "page_views"=>38, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Targeting_MMSET_in_t_4_14_tumors_prolongs_survival_/1162428", "title"=>"Targeting MMSET in t(4;14)+ tumors prolongs survival.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-04 04:53:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/1663081"], "description"=>"<p>(A) Venn diagram showing overlap of genes bound at their promoters by EZH2 in NTKO (blue) and TKO (yellow) cells. (B) UCSC genome browser display of H3K27me3 (top, gray) and EZH2 binding (bottom, red) in NTKO cells. (C) UCSC genome browser display of EZH2 ChIP-seq tracks in NTKO (top, red) and TKO (bottom, green) cells associated with MMSET-repressed genes, <i>CDCA7</i> (left) and <i>DLL4</i> (right). (D) Heat map of over-represented gene categories among genes bound by EZH2 in either NTKO cells, TKO cells or both cell types. Enrichment was measured using iPAGE analysis <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004566#pgen.1004566-Goodarzi1\" target=\"_blank\">[74]</a>. (E) Motif analysis using HOMER <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004566#pgen.1004566-Heinz1\" target=\"_blank\">[73]</a> identified conserved sequences bound by EZH2 in NTKO cells, TKO cells or both cell types. (F) Relative cell number of MMSET-high and MMSET-low cells treated with indicated doses of the EZH2 small molecule inhibitor (GSK343). Inactive compound, GSK669, was used as a control. Graph represents four independent experiments +/− standard deviation. (G) Quantitative RT-PCR measurement of miR-126* expression in KMS11 cells treated with GSK669 or GSK 343. Graph represents average expression from three independent experiments +/− standard deviation (* p<0.05). (H) Representative immunoblot of nuclear extracts from MMSET-high (KMS11) and MMSET-low (TKO) cells treated for seven days with 2 µM EZH2 inhibitor (GSK343) or inactive control (GSK669). This experiment was performed in biological triplicate.</p>", "links"=>[], "tags"=>["phd", "H 3K methylation", "genomic loci exhibit", "H 3K Methylation Overexpression", "lysine 27 trimethylation", "EZH 2 histone methyltransferase", "H 3K", "MMSET catalyzes dimethylation", "histone methylation changes", "histone methyltransferase MMSET", "EZH 2 inhibition", "myeloma", "histone H 3"], "article_id"=>1162425, "categories"=>["Uncategorised"], "users"=>["Relja Popovic", "Eva Martinez-Garcia", "Eugenia G. Giannopoulou", "Quanwei Zhang", "Qingyang Zhang", "Teresa Ezponda", "Mrinal Y. Shah", "Yupeng Zheng", "Christine M. Will", "Eliza C. Small", "Youjia Hua", "Marinka Bulic", "Yanwen Jiang", "Matteo Carrara", "Raffaele A. Calogero", "William L. Kath", "Neil L. Kelleher", "Ji-Ping Wang", "Olivier Elemento", "Jonathan D. Licht"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004566.g004", "stats"=>{"downloads"=>5, "page_views"=>256, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MMSET_alters_EZH2_binding_in_t_4_14_myeloma_cells_/1162425", "title"=>"MMSET alters EZH2 binding in t(4;14)+ myeloma cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-04 04:53:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/1663079"], "description"=>"<p>(A) Dot plot representing differentially expressed genes in NTKO and TKO cells from the microarray data. Genes upregulated and downregulated by MMSET (p<0.002) are in red (522 genes) and green (308 genes), respectively; genes that do not change expression are in dark blue (10,884 genes) and genes that are not expressed (2,234 genes) in either cell line are light blue. (B) Tag density profile of H3K36me2 distribution across different gene groups from A. Ratio between the number of reads in NTKO and TKO cells is presented on the y-axis. (C) Quantitative RT-PCR validation of several genes upregulated and downregulated by MMSET overexpression. (D) Heatmaps of H3K36me3 distribution between NTKO (left) and TKO (right) cells. Data were plotted as in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004566#pgen-1004566-g001\" target=\"_blank\">Figure 1B</a>. (E) Density tracks for H3K36me2 and H3K36me3 on a gene upregulated by MMSET (<i>CR2</i> - upper panel) and a gene downregulated by MMSET overexpression (<i>DLL4</i> – lower panel). H3K36me2 tracks are in red and green for NTKO and TKO cells, respectively; H3K36me3 tracks are in blue (NTKO) and fuchsia (TKO).</p>", "links"=>[], "tags"=>["phd", "H 3K methylation", "genomic loci exhibit", "H 3K Methylation Overexpression", "lysine 27 trimethylation", "EZH 2 histone methyltransferase", "H 3K", "MMSET catalyzes dimethylation", "histone methylation changes", "histone methyltransferase MMSET", "EZH 2 inhibition", "myeloma", "histone H 3"], "article_id"=>1162423, "categories"=>["Uncategorised"], "users"=>["Relja Popovic", "Eva Martinez-Garcia", "Eugenia G. Giannopoulou", "Quanwei Zhang", "Qingyang Zhang", "Teresa Ezponda", "Mrinal Y. Shah", "Yupeng Zheng", "Christine M. Will", "Eliza C. Small", "Youjia Hua", "Marinka Bulic", "Yanwen Jiang", "Matteo Carrara", "Raffaele A. Calogero", "William L. Kath", "Neil L. Kelleher", "Ji-Ping Wang", "Olivier Elemento", "Jonathan D. Licht"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004566.g002", "stats"=>{"downloads"=>1, "page_views"=>22, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_High_levels_of_MMSET_lead_to_altered_gene_expression_/1162423", "title"=>"High levels of MMSET lead to altered gene expression.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-04 04:53:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/1663080"], "description"=>"<p>(A) Tag density profile of H3K27me3 distribution across different gene groups from <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004566#pgen-1004566-g002\" target=\"_blank\">Figure 2A</a>. The ratio between read numbers in NTKO and TKO cells is presented on the y-axis. (B) UCSC genome browser display of H3K27me3 density tracks surrounding the transcription start site of two MMSET activated genes, <i>CA2</i> (top) and <i>CR2</i> (bottom). (C) GSEA analysis of genes upregulated by MMSET shows enrichment of previously identified EZH2 target genes. (D) UCSC genome browser display of H3K27me3 density tracks surrounding the transcription start site of two MMSET repressed genes, <i>DLL4</i> (top) and <i>CDCA7</i> (bottom). (E) ChIP-qPCR for H3K27me3 on <i>CDCA7</i> locus. Methylation enrichment was tested on the promoter (TSS) and on the regions upstream (5′) and downstream (3′) from the TSS. Two independent biological replicates are shown. (F) UCSC genome browser of H3K27me3 enrichment on non-expressed genes of the <i>HOXC</i> cluster (left) and ChIP-qPCR for H3K27me3 on the <i>HOXC10</i> locus (right). Two independent biological replicates are shown. (G) Tag density profile of H3K36me2 (left), H3K36me3 (middle) and H3K27me3 (right) distribution of differentially expressed genes in TKO cells.</p>", "links"=>[], "tags"=>["phd", "H 3K methylation", "genomic loci exhibit", "H 3K Methylation Overexpression", "lysine 27 trimethylation", "EZH 2 histone methyltransferase", "H 3K", "MMSET catalyzes dimethylation", "histone methylation changes", "histone methyltransferase MMSET", "EZH 2 inhibition", "myeloma", "histone H 3"], "article_id"=>1162424, "categories"=>["Uncategorised"], "users"=>["Relja Popovic", "Eva Martinez-Garcia", "Eugenia G. Giannopoulou", "Quanwei Zhang", "Qingyang Zhang", "Teresa Ezponda", "Mrinal Y. Shah", "Yupeng Zheng", "Christine M. Will", "Eliza C. Small", "Youjia Hua", "Marinka Bulic", "Yanwen Jiang", "Matteo Carrara", "Raffaele A. Calogero", "William L. Kath", "Neil L. Kelleher", "Ji-Ping Wang", "Olivier Elemento", "Jonathan D. Licht"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004566.g003", "stats"=>{"downloads"=>2, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MMSET_alters_genome_wide_patterns_of_H3K27me3_methylation_/1162424", "title"=>"MMSET alters genome-wide patterns of H3K27me3 methylation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-04 04:53:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/1663078"], "description"=>"<p>(A) Loss of MMSET expression in t(4;14)+ cells depletes H3K36 methylation and increases H3K27 methylation. Immunoblot of nuclear extracts from t(4;14)+ KMS11 cells with inactivated translocated (TKO) or wild-type (NTKO) <i>MMSET</i> allele were probed using antibodies for MMSET, H3K36me2, H3K27me3 and total H4 as control. (B) Heatmaps of H3K36me2 distribution between NTKO (left) and TKO (right) cells. On the y-axis, genes were ranked based on their expression level from high (top) to low (bottom) and on the x-axis, normalized read density from ChIP-seq experiments was plotted in gene bodies and 10 kb upstream and downstream from the transcription start (TSS) and end (TES) sites. (C) MMSET alters H3K36me2 distribution in intragenic (top) and intergenic (bottom) regions. (Top) Average read density across 15,386 genes in NTKO (left, red) and TKO (right, green) cells. (Middle) UCSC genome browser view of the H3K36me2 distribution on a representative locus (<i>BTF3</i>) in NTKO and TKO cells. (Bottom) Average normalized tag density of H3K36me2 in 6,172 intergenic regions in NTKO (left) and TKO (right) cells. (D) Representative UCSC genome browser view of the H3K36me2 distribution on chromosome 8 of NTKO (red) and TKO (green) cells. Top panel encompasses a gene-rich region of the chromosome and the bottom insert represents a 1MB region of the 8q24 gene desert. (E) ChIP-qPCR for H3K36me2 on the <i>BTF3</i> locus. Methylation enrichment was tested 5 kb upstream of the TSS (5′) and at the TSS (right). Two independent biological replicates are shown.</p>", "links"=>[], "tags"=>["phd", "H 3K methylation", "genomic loci exhibit", "H 3K Methylation Overexpression", "lysine 27 trimethylation", "EZH 2 histone methyltransferase", "H 3K", "MMSET catalyzes dimethylation", "histone methylation changes", "histone methyltransferase MMSET", "EZH 2 inhibition", "myeloma", "histone H 3"], "article_id"=>1162422, "categories"=>["Uncategorised"], "users"=>["Relja Popovic", "Eva Martinez-Garcia", "Eugenia G. Giannopoulou", "Quanwei Zhang", "Qingyang Zhang", "Teresa Ezponda", "Mrinal Y. Shah", "Yupeng Zheng", "Christine M. Will", "Eliza C. Small", "Youjia Hua", "Marinka Bulic", "Yanwen Jiang", "Matteo Carrara", "Raffaele A. Calogero", "William L. Kath", "Neil L. Kelleher", "Ji-Ping Wang", "Olivier Elemento", "Jonathan D. Licht"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004566.g001", "stats"=>{"downloads"=>2, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MMSET_overexpression_alters_normal_H3K36me2_distribution_/1162422", "title"=>"MMSET overexpression alters normal H3K36me2 distribution.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-04 04:53:59"}

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