Dual DNA Methylation Patterns in the CNS Reveal Developmentally Poised Chromatin and Monoallelic Expression of Critical Genes
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{"title"=>"Dual DNA methylation patterns in the CNS reveal developmentally poised chromatin and monoallelic expression of critical genes", "type"=>"journal", "authors"=>[{"first_name"=>"Jinhui", "last_name"=>"Wang", "scopus_author_id"=>"18041416400"}, {"first_name"=>"Zuzana", "last_name"=>"Valo", "scopus_author_id"=>"6507542876"}, {"first_name"=>"Chauncey W.", "last_name"=>"Bowers", "scopus_author_id"=>"7202781590"}, {"first_name"=>"David D.", "last_name"=>"Smith", "scopus_author_id"=>"56424029200"}, {"first_name"=>"Zheng", "last_name"=>"Liu", "scopus_author_id"=>"55784919000"}, {"first_name"=>"Judith", "last_name"=>"Singer-Sam", "scopus_author_id"=>"7004263085"}], "year"=>2010, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"21079792", "sgr"=>"78149477553", "doi"=>"10.1371/journal.pone.0013843", "scopus"=>"2-s2.0-78149477553", "pui"=>"359941794", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "issn"=>"19326203"}, "id"=>"aaba6869-0fbf-3609-974b-b60423a2411a", "abstract"=>"As a first step towards discovery of genes expressed from only one allele in the CNS, we used a tiling array assay for DNA sequences that are both methylated and unmethylated (the MAUD assay). We analyzed regulatory regions of the entire mouse brain transcriptome, and found that approximately 10% of the genes assayed showed dual DNA methylation patterns. They include a large subset of genes that display marks of both active and silent, i.e., poised, chromatin during development, consistent with a link between differential DNA methylation and lineage-specific differentiation within the CNS. Sixty-five of the MAUD hits and 57 other genes whose function is of relevance to CNS development and/or disorders were tested for allele-specific expression in F(1) hybrid clonal neural stem cell (NSC) lines. Eight MAUD hits and one additional gene showed such expression. They include Lgi1, which causes a subtype of inherited epilepsy that displays autosomal dominance with incomplete penetrance; Gfra2, a receptor for glial cell line-derived neurotrophic factor GDNF that has been linked to kindling epilepsy; Unc5a, a netrin-1 receptor important in neurodevelopment; and Cspg4, a membrane chondroitin sulfate proteoglycan associated with malignant melanoma and astrocytoma in human. Three of the genes, Camk2a, Kcnc4, and Unc5a, show preferential expression of the same allele in all clonal NSC lines tested. The other six genes show a stochastic pattern of monoallelic expression in some NSC lines and bi-allelic expression in others. These results support the estimate that 1-2% of genes expressed in the CNS may be subject to allelic exclusion, and demonstrate that the group includes genes implicated in major disorders of the CNS as well as neurodevelopment.", "link"=>"http://www.mendeley.com/research/dual-dna-methylation-patterns-cns-reveal-developmentally-poised-chromatin-monoallelic-expression-cri", "reader_count"=>46, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>3, "Researcher"=>15, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>2, "Student > Master"=>4, "Student > Bachelor"=>1, "Lecturer"=>1, "Professor"=>6, "Other"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>3, "Researcher"=>15, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>2, "Student > Master"=>4, "Student > Bachelor"=>1, "Lecturer"=>1, "Professor"=>6, "Other"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>4, "Agricultural and Biological Sciences"=>35, "Medicine and Dentistry"=>4, "Neuroscience"=>1, "Engineering"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Neuroscience"=>{"Neuroscience"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>35}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"Netherlands"=>1, "United States"=>1, "Japan"=>1, "Denmark"=>1, "Italy"=>1, "United Kingdom"=>1}, "group_count"=>2}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/408894", "https://ndownloader.figshare.com/files/408983", "https://ndownloader.figshare.com/files/409055", "https://ndownloader.figshare.com/files/409085", "https://ndownloader.figshare.com/files/409160", "https://ndownloader.figshare.com/files/409184", "https://ndownloader.figshare.com/files/409214", "https://ndownloader.figshare.com/files/409223", "https://ndownloader.figshare.com/files/409265"], "description"=>"<div><p>As a first step towards discovery of genes expressed from only one allele in the CNS, we used a tiling array assay for DNA sequences that are both methylated and unmethylated (the MAUD assay). We analyzed regulatory regions of the entire mouse brain transcriptome, and found that approximately 10% of the genes assayed showed dual DNA methylation patterns. They include a large subset of genes that display marks of both active and silent, i.e., poised, chromatin during development, consistent with a link between differential DNA methylation and lineage-specific differentiation within the CNS. Sixty-five of the MAUD hits and 57 other genes whose function is of relevance to CNS development and/or disorders were tested for allele-specific expression in F<sub>1</sub> hybrid clonal neural stem cell (NSC) lines. Eight MAUD hits and one additional gene showed such expression. They include <em>Lgi1</em>, which causes a subtype of inherited epilepsy that displays autosomal dominance with incomplete penetrance; <em>Gfra2,</em> a receptor for glial cell line-derived neurotrophic factor GDNF that has been linked to kindling epilepsy; <em>Unc5a</em>, a netrin-1 receptor important in neurodevelopment; and <em>Cspg4,</em> a membrane chondroitin sulfate proteoglycan associated with malignant melanoma and astrocytoma in human. Three of the genes, <em>Camk2a, Kcnc4</em>, and <em>Unc5a</em>, show preferential expression of the same allele in all clonal NSC lines tested. The other six genes show a stochastic pattern of monoallelic expression in some NSC lines and bi-allelic expression in others. These results support the estimate that 1–2% of genes expressed in the CNS may be subject to allelic exclusion, and demonstrate that the group includes genes implicated in major disorders of the CNS as well as neurodevelopment.</p></div>", "links"=>[], "tags"=>["dual", "dna", "methylation", "patterns", "cns", "developmentally", "poised", "chromatin", "monoallelic", "genes"], "article_id"=>140780, "categories"=>["Genetics"], "users"=>["Jinhui Wang", "Zuzana Valo", "Chauncey W. Bowers", "David D. Smith", "Zheng Liu", "Judith Singer-Sam"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0013843.s001", "https://dx.doi.org/10.1371/journal.pone.0013843.s002", "https://dx.doi.org/10.1371/journal.pone.0013843.s003", "https://dx.doi.org/10.1371/journal.pone.0013843.s004", "https://dx.doi.org/10.1371/journal.pone.0013843.s005", "https://dx.doi.org/10.1371/journal.pone.0013843.s006", "https://dx.doi.org/10.1371/journal.pone.0013843.s007", "https://dx.doi.org/10.1371/journal.pone.0013843.s008", "https://dx.doi.org/10.1371/journal.pone.0013843.s009"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Dual_DNA_Methylation_Patterns_in_the_CNS_Reveal_Developmentally_Poised_Chromatin_and_Monoallelic_Expression_of_Critical_Genes/140780", "title"=>"Dual DNA Methylation Patterns in the CNS Reveal Developmentally Poised Chromatin and Monoallelic Expression of Critical Genes", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2010-11-04 00:13:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/820341"], "description"=>"<p>A. Experimental design. B. Reproducibility of the assay. Results for three biological replicates are shown. For each mouse forebrain sample, two hybridizations were carried out, one to detect unmethylated DNA (top row), and one to detect methylated DNA (bottom row). Each of the six plots shows the microarray signals (log2 ratio of experimental sample to control) for mouse 1 vs. mouse 2, mouse 1 vs. mouse 3 and mouse 2 vs. mouse 3 as indicated. For each combination, the correlation between mice is shown (r), as well as the two-way intra-class correlation for the presence or absence of peaks. A <i>P</i> value of<0.0001 demonstrated good reproducibility for multiple independent samples.</p>", "links"=>[], "tags"=>["maud"], "article_id"=>490707, "categories"=>["Genetics"], "users"=>["Jinhui Wang", "Zuzana Valo", "Chauncey W. Bowers", "David D. Smith", "Zheng Liu", "Judith Singer-Sam"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0013843.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Overview_of_the_MAUD_assay_/490707", "title"=>"Overview of the MAUD assay.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-11-04 00:11:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/820488"], "description"=>"<p>The X-axis shows probe signals aligned with the nucleotide position and restriction sites along mouse Chr 2 at the <i>Gnas</i> locus (<a href=\"http://genome.ucsc.edu\" target=\"_blank\">http://genome.ucsc.edu</a>) <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0013843#pone.0013843-Kent1\" target=\"_blank\">[49]</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0013843#pone.0013843-Rhead1\" target=\"_blank\">[50]</a>. The Y-axis shows the log2 ratio of signal intensities for unmethylated vs. control DNA (purple bars), and methylated vs. control DNA (blue bars). The triplicate tracks show results for three biological replicates; for each track, Y<sub>max</sub> is 7.2. Below the track blue vertical lines indicate Csp6I restriction sites; black vertical lines show the location of the restriction sites for HpaII AciI and HpyCH4IV. The origin of the line with blue arrows indicates the transcription start site and orientation of the differentially methylated <i>Gnas</i> gene. Nine of eleven differentially methylated control genes were detected by the MAUD assay (see text).</p>", "links"=>[], "tags"=>["maud"], "article_id"=>490855, "categories"=>["Genetics"], "users"=>["Jinhui Wang", "Zuzana Valo", "Chauncey W. Bowers", "David D. Smith", "Zheng Liu", "Judith Singer-Sam"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0013843.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Representative_results_of_the_MAUD_assay_/490855", "title"=>"Representative results of the MAUD assay.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-11-04 00:14:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/820607"], "description"=>"<p>The chromatograms show sequencing results following RT-PCR of RNA from B6 or JF1 brain and representative F<sub>1</sub> hybrid NSC clonal lines, as indicated. Complete results are shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0013843#pone.0013843.s004\" target=\"_blank\">Figure S4</a>, and summarized in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0013843#pone-0013843-t001\" target=\"_blank\">Table 1</a>.</p>", "links"=>[], "tags"=>["allele-specific", "clonal", "nsc"], "article_id"=>490972, "categories"=>["Genetics"], "users"=>["Jinhui Wang", "Zuzana Valo", "Chauncey W. Bowers", "David D. Smith", "Zheng Liu", "Judith Singer-Sam"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0013843.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Patterns_of_allele_specific_expression_of_Gfra2_and_Unc5a_in_clonal_NSC_lines_/490972", "title"=>"Patterns of allele-specific expression of <i>Gfra2</i> and <i>Unc5a</i> in clonal NSC lines.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-11-04 00:16:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/820720"], "description"=>"<p>(A). Allele-specific expression. <i>Top row</i>; SNPs between the two parental mouse strains. The chromatogram at the right shows the presence of both alleles in DNA from the NSC line 2A1. Both alleles were also present in lines 4A5 and 4B3 (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0013843#pone.0013843.s004\" target=\"_blank\">Figure S4</a>). <i>Middle and bottom rows:</i> Allele-specific expression for the clonal NSC lines indicated. (B). Relative expression in NSC lines showing bi-allelic or monoallelic expression. The latter are marked with an asterisk. Results were obtained by real-time RT-PCR. <i>Y-axis,</i> expression levels of <i>Cspg4</i> normalized relative to <i>Pgk1</i>. For each sample, error bars indicate the SEM (<i>n</i> = 3 technical replicates).</p>", "links"=>[], "tags"=>["clonal", "nsc"], "article_id"=>491089, "categories"=>["Genetics"], "users"=>["Jinhui Wang", "Zuzana Valo", "Chauncey W. Bowers", "David D. Smith", "Zheng Liu", "Judith Singer-Sam"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0013843.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_Cspg4_in_clonal_NSC_lines_/491089", "title"=>"Expression of <i>Cspg4</i> in clonal NSC lines.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-11-04 00:18:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/820830"], "description"=>"<p>(A). MAUD assay results. Duplicate tracks (<a href=\"http://genome.ucsc.edu\" target=\"_blank\">http://genome.ucsc.edu</a>) show results for two mouse brain samples. The light green box shows the location of a small CpG island. (B). Location of chromatin IP signals in mouse ES cells. Top to bottom, H3K4me1, H3K4me2, H3K4me3 (green), H3K27me3 (red) <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0013843#pone.0013843-Mikkelsen1\" target=\"_blank\">[23]</a>.</p>", "links"=>[], "tags"=>["promoter"], "article_id"=>491197, "categories"=>["Genetics"], "users"=>["Jinhui Wang", "Zuzana Valo", "Chauncey W. Bowers", "David D. Smith", "Zheng Liu", "Judith Singer-Sam"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0013843.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Annotation_of_the_Cspg4_promoter_region_/491197", "title"=>"Annotation of the <i>Cspg4</i> promoter region.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-11-04 00:19:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/820926"], "description"=>"<p>The letters ‘B’ and ‘J’ denote values corresponding to preferential (80% to 100%) expression of the B6 or JF1 allele, respectively. See <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0013843#pone.0013843.s004\" target=\"_blank\">Figure S4</a> for detailed results, including technical replicates and standard errors. Asterisks denote concordance with allele-specific expression in NSCs:</p><p>*<i>P</i><0.05;</p><p>**<i>P</i><0.0001.</p><p>∧only JF1 allele present.</p><p><i>n.d</i>., not detectable.</p>", "links"=>[], "tags"=>["undifferentiated", "nscs", "differentiated", "neurons"], "article_id"=>491290, "categories"=>["Genetics"], "users"=>["Jinhui Wang", "Zuzana Valo", "Chauncey W. Bowers", "David D. Smith", "Zheng Liu", "Judith Singer-Sam"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0013843.t001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Allele_specific_expression_in_undifferentiated_NSCs_and_NSCs_differentiated_to_neurons_and_astrocytes_/491290", "title"=>"Allele-specific expression in undifferentiated NSCs, and NSCs differentiated to neurons and astrocytes.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2010-11-04 00:21:30"}

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