Genetic Variation Stimulated by Epigenetic Modification
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{"title"=>"Genetic variation stimulated by epigenetic modification", "type"=>"journal", "authors"=>[{"first_name"=>"W. Jason", "last_name"=>"Cummings", "scopus_author_id"=>"7006737676"}, {"first_name"=>"David W.", "last_name"=>"Bednarski", "scopus_author_id"=>"9133340500"}, {"first_name"=>"Nancy", "last_name"=>"Maizels", "scopus_author_id"=>"7005558734"}], "year"=>2008, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"19115012", "sgr"=>"58149187871", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0004075", "scopus"=>"2-s2.0-58149187871", "pui"=>"354030432"}, "id"=>"c36ab4ea-2b56-3613-afa0-aa74865bdfff", "abstract"=>"Homologous recombination is essential for maintaining genomic integrity. A common repair mechanism, it uses a homologous or homeologous donor as a template for repair of a damaged target gene. Such repair must be regulated, both to identify appropriate donors for repair, and to avoid excess or inappropriate recombination. We show that modifications of donor chromatin structure can promote homology-directed repair. These experiments demonstrate that either the activator VP16 or the histone chaperone, HIRA, accelerated gene conversion approximately 10-fold when tethered within the donor array for Ig gene conversion in the chicken B cell line DT40. VP16 greatly increased levels of acetylated histones H3 and H4, while tethered HIRA did not affect histone acetylation, but caused an increase in local nucleosome density and levels of histone H3.3. Thus, epigenetic modification can stimulate genetic variation. The evidence that distinct activating modifications can promote similar functional outcomes suggests that a variety of chromatin changes may regulate homologous recombination, and that disregulation of epigenetic marks may have deleterious genetic consequences.", "link"=>"http://www.mendeley.com/research/genetic-variation-stimulated-epigenetic-modification", "reader_count"=>36, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>12, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>15, "Student > Master"=>4, "Professor"=>3}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>12, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>15, "Student > Master"=>4, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>3, "Agricultural and Biological Sciences"=>27, "Medicine and Dentistry"=>1, "Psychology"=>1, "Chemistry"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Chemistry"=>{"Chemistry"=>1}, "Psychology"=>{"Psychology"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>27}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>1}, "Environmental Science"=>{"Environmental Science"=>1}}, "reader_count_by_country"=>{"France"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/913063"], "description"=>"<p>Summary of sequences of Vλ regions carrying unique mutations from DT40 PolyLacO-λ GFP-LacI-VP16 (n = 92), and DT40 PolyLacO-λ HIRA-LacI (n = 137) transfectants. Data derived from at least two independent transfections. DT40 PolyLacO-λ GFP-LacI {Cummings, 2007 #776} is included for comparison.</p>", "links"=>[], "tags"=>["tethered", "hira", "vp16"], "article_id"=>583520, "categories"=>["Molecular Biology", "Biochemistry", "Immunology", "Genetics", "Cell Biology"], "users"=>["W. Jason Cummings", "David W. Bednarski", "Nancy Maizels"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0004075.t001", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_Tethered_HIRA_and_VP16_on_Gene_Conversion_/583520", "title"=>"Effect of Tethered HIRA and VP16 on Gene Conversion.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-12-30 00:58:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/912591"], "description"=>"<p>(A) Quantitation of enrichment of acetylated H3 (AcH3) at Igλ in DT40 PolyLacO-λ GFP-LacI and DT40 PolyLacO-λ GFP-LacI-VP16 transfectants. Sites interrogated are shown below. Enrichment assayed by ChIP is expressed relative to the total DNA input control, ±standard deviation of three or more separate amplifications of increasing amounts of template DNA. (B) Quantitation of enrichment of acetylated H4 (AcH4) at Igλ in DT40 PolyLacO-λ GFP-LacI and DT40 PolyLacO-λ GFP-LacI-VP16 transfectants, expressed relative to DNA input control. Notations as in Panel A. (C) Flow cytometry of individual expanded clones of DT40 PolyLacO-λ GFP-LacI and DT40 PolyLacO-λ GFP-LacI-VP16 transfectants, stained with anti-IgM. (D) Median sIgM loss in panels of independent DT40 PolyLacO-λ GFP-LacI-VP16 transfectants (n = 64), normalized to DT40 PolyLacO-Vλ GFP-LacI transfectants (n = 27). The figure shows combined data from at least two independent transfectants for each construct. The fold increase relative to control DT40 PolyLacO-Vλ GFP-LacI transfectants is shown below.</p>", "links"=>[], "tags"=>["vp16", "increases", "ach3", "ach4", "levels", "accelerates", "ig"], "article_id"=>583041, "categories"=>["Molecular Biology", "Biochemistry", "Immunology", "Genetics", "Cell Biology"], "users"=>["W. Jason Cummings", "David W. Bednarski", "Nancy Maizels"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0004075.g002", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Tethered_VP16_Increases_AcH3_and_AcH4_Levels_and_Accelerates_Ig_Gene_Diversification_/583041", "title"=>"Tethered VP16 Increases AcH3 and AcH4 Levels and Accelerates Ig Gene Diversification.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-30 00:50:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/912454"], "description"=>"<p>(A) Schematic diagram of the rearranged chicken Igλ locus in DT40, with polymerized lactose operator (PolyLacO) inserted between ψVλ17–20. Promoter, P; leader, L; rearranged variable region, Vλ–Jλ; constant region, Cλ. (B) Fluorescent image of DT40 PolyLacO-λ GFP-LacI-VP16 transfectants. Nuclei were counterstained with DAPI (blue). Arrows indicate GFP-LacI-VP16 bound to Igλ. Bar, 15 µm. (C) Cell cycle profiles of DT40 PolyLacO-λ GFP-LacI and DT40 PolyLacO-λ GFP-LacI-VP16 transfectants. (D) Quantitation of RT-PCR comparison of Vλ transcript levels in DT40 PolyLacO-λ GFP-LacI and DT40 PolyLacO-λ GFP-LacI-VP16 transfectants. Values represent the average of at least 2 amplifications that were normalized to the average value for DT40 PolyLacO-λ GFP-LacI.</p>", "links"=>[], "tags"=>["gfp-laci-vp16", "dt40"], "article_id"=>582915, "categories"=>["Molecular Biology", "Biochemistry", "Immunology", "Genetics", "Cell Biology"], "users"=>["W. Jason Cummings", "David W. Bednarski", "Nancy Maizels"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0004075.g001", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Tethering_of_GFP_LacI_VP16_to_the_968_V_955_Array_in_DT40_PolyLacO_955_R_/582915", "title"=>"Tethering of GFP-LacI-VP16 to the ψVλ Array in DT40 PolyLacO-λR.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-30 00:48:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/912961"], "description"=>"<p>(A) Quantitation of enrichment of AcH3 (above) and AcH4 (below) at Igλ in DT40 PolyLacO-λ GFP-LacI and DT40 PolyLacO-λ HIRA-LacI transfectants. Enrichment assayed by ChIP is expressed relative to the total DNA input control, ±standard deviation of three or more separate amplifications of increasing amounts of template DNA. (B) Quantitation of ChIP analysis of enrichment of H3.3 (FLAG-H3.3) and pan H3 at ψVλ17<sub>R</sub> in DT40 PolyLacO-λ and DT40 PolyLacO-λ HIRA-LacI cells expressing H3.3-FLAG, normalized to enrichment in DT40 PolyLacO-λ. Bars are shown ±standard deviation of four separate amplifications of increasing amounts of template DNA. (C) Southern blot analysis of the PolyLacO region in DT40 PolyLacO-λ GFP-LacI, DT40 PolyLacO-λ GFP-LacI-VP16 and DT40 PolyLacO-λ HIRA-LacI transfectants, following digestion of chromatin with micrococcal nuclease (MNase). No Mnase, (-). Numbers at the right denote nucleosome multimers. (D) Model of how elevated histone deposition could diminish size heterogeneity of protected nucleosome fragments. A defined region of DNA experiences nucleosome loading at increased density. Grey arrowheads indicate a range of cleavable positions, which will result in size heterogeneity of the protected fragments; dark arrowheads indicate restricted range of cleavable sites.</p>", "links"=>[], "tags"=>["hira", "enriches", "levels", "alters", "chromatin"], "article_id"=>583415, "categories"=>["Molecular Biology", "Biochemistry", "Immunology", "Genetics", "Cell Biology"], "users"=>["W. Jason Cummings", "David W. Bednarski", "Nancy Maizels"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0004075.g005", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Tethered_HIRA_Enriches_Local_Levels_of_H3_3_and_Alters_Local_Chromatin_Structure_/583415", "title"=>"Tethered HIRA Enriches Local Levels of H3.3 and Alters Local Chromatin Structure.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-30 00:56:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/912766"], "description"=>"<p>Summary of a representative chromatin immunoprecipitation experiment, assaying enrichment of the H3.3 histone variant. Sites interrogated were: a region approximately 1 kb upstream of the ψVλ array (flank); the region between ψVλ1 and Vλ; ψVλ1; ψVλ5; ψVλ13; ψVλ18; ψVλ24; ψVλ25; and the rearranged Vλ<sub>R</sub> allele. Bars indicate standard deviation of at least three separate amplifications.</p>", "links"=>[], "tags"=>["histone", "variant", "enriched", "dt40"], "article_id"=>583223, "categories"=>["Molecular Biology", "Biochemistry", "Immunology", "Genetics", "Cell Biology"], "users"=>["W. Jason Cummings", "David W. Bednarski", "Nancy Maizels"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0004075.g003", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_H3_3_Histone_Variant_is_Enriched_at_the_DT40_Ig_955_Locus_/583223", "title"=>"The H3.3 Histone Variant is Enriched at the DT40 Igλ Locus.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-30 00:53:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/912854"], "description"=>"<p>(A) Western blot analysis of expression of GFP-LacI or HIRA-LacI in indicated transfectants. Two individual clones are shown for HIRA-LacI expression. Assay was performed by blotting with anti-LacI antibodies (for detection of GFP-LacI and HIRA-LacI), relative to β-actin control. (B) Cell cycle profile of DT40 PolyLacO-λ GFP-LacI and DT40 PolyLacO-λ HIRA-LacI transfectants. (C) Quantitation of RT-PCR comparison of Vλ transcript levels in DT40 PolyLacO-λ GFP-LacI and DT40 PolyLacO-λ HIRA-LacI transfectants. Values represent the average of at least 2 amplifications that were normalized to the average value for DT40 PolyLacO-λ GFP-LacI. (D) Flow cytometry of individual expanded clones in representative populations of DT40 PolyLacO-λ GFP-LacI and DT40 PolyLacO-λ HIRA-LacI transfectants, stained with anti-IgM. (E) Median sIgM loss in panels of independent DT40 PolyLacO-λ HIRA-LacI (n = 48), and DT40 HIRA transfectants (n = 24), normalized to DT40 PolyLacO-λ GFP-LacI transfectants (n = 24). The figure shows combined data from at least two independent transfectants for each construct. The fold increase relative to control DT40 PolyLacO-λ GFP-LacI transfectants is shown below.</p>", "links"=>[], "tags"=>["hira", "accelerates", "ig"], "article_id"=>583309, "categories"=>["Molecular Biology", "Biochemistry", "Immunology", "Genetics", "Cell Biology"], "users"=>["W. Jason Cummings", "David W. Bednarski", "Nancy Maizels"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0004075.g004", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Tethered_HIRA_Accelerates_Ig_Gene_Diversification_/583309", "title"=>"Tethered HIRA Accelerates Ig Gene Diversification.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-30 00:55:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/451610", "https://ndownloader.figshare.com/files/451716"], "description"=>"<div><p>Homologous recombination is essential for maintaining genomic integrity. A common repair mechanism, it uses a homologous or homeologous donor as a template for repair of a damaged target gene. Such repair must be regulated, both to identify appropriate donors for repair, and to avoid excess or inappropriate recombination. We show that modifications of donor chromatin structure can promote homology-directed repair. These experiments demonstrate that either the activator VP16 or the histone chaperone, HIRA, accelerated gene conversion approximately 10-fold when tethered within the donor array for Ig gene conversion in the chicken B cell line DT40. VP16 greatly increased levels of acetylated histones H3 and H4, while tethered HIRA did not affect histone acetylation, but caused an increase in local nucleosome density and levels of histone H3.3. Thus, epigenetic modification can stimulate genetic variation. The evidence that distinct activating modifications can promote similar functional outcomes suggests that a variety of chromatin changes may regulate homologous recombination, and that disregulation of epigenetic marks may have deleterious genetic consequences.</p></div>", "links"=>[], "tags"=>["stimulated", "epigenetic", "modification"], "article_id"=>149006, "categories"=>["Molecular Biology", "Biochemistry", "Immunology", "Genetics", "Cell Biology"], "users"=>["W. Jason Cummings", "David W. Bednarski", "Nancy Maizels"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0004075.s001", "https://dx.doi.org/10.1371/journal.pone.0004075.s002"], "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Genetic_Variation_Stimulated_by_Epigenetic_Modification/149006", "title"=>"Genetic Variation Stimulated by Epigenetic Modification", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2008-12-30 02:30:06"}

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  • {"unique-ip"=>"5", "full-text"=>"6", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}
  • {"unique-ip"=>"7", "full-text"=>"9", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2019", "month"=>"8"}
  • {"unique-ip"=>"6", "full-text"=>"4", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"9"}
  • {"unique-ip"=>"4", "full-text"=>"4", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"10"}
  • {"unique-ip"=>"8", "full-text"=>"4", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"6", "cited-by"=>"0", "year"=>"2019", "month"=>"12"}
  • {"unique-ip"=>"9", "full-text"=>"8", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"4", "cited-by"=>"0", "year"=>"2020", "month"=>"2"}
  • {"unique-ip"=>"5", "full-text"=>"3", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"4", "cited-by"=>"0", "year"=>"2020", "month"=>"3"}
  • {"unique-ip"=>"3", "full-text"=>"1", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"4"}
  • {"unique-ip"=>"2", "full-text"=>"3", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"5"}
  • {"unique-ip"=>"6", "full-text"=>"6", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"6"}
  • {"unique-ip"=>"3", "full-text"=>"2", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"7"}
  • {"unique-ip"=>"1", "full-text"=>"1", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"8"}
  • {"unique-ip"=>"2", "full-text"=>"2", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"10"}
  • {"unique-ip"=>"4", "full-text"=>"3", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"11"}
  • {"unique-ip"=>"2", "full-text"=>"0", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"12"}
  • {"unique-ip"=>"5", "full-text"=>"4", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2021", "month"=>"1"}

Relative Metric

{"start_date"=>"2008-01-01T00:00:00Z", "end_date"=>"2008-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences", "average_usage"=>[324, 674, 863, 1015, 1146, 1259, 1360, 1452, 1540, 1621, 1704, 1776, 1843, 1905, 1968, 2029, 2097, 2162, 2233, 2289, 2352, 2412, 2476, 2538, 2601, 2655, 2714, 2777, 2841, 2894, 2946, 2998, 3047, 3103, 3151, 3201, 3258, 3317, 3369, 3424, 3471, 3521, 3583, 3625, 3687, 3743, 3788, 3838, 3896, 3953, 4015, 4075, 4148, 4201, 4275, 4347, 4420, 4486, 4535, 4592, 4660, 4731, 4792, 4845, 4901, 4971, 5027, 5089, 5148, 5200, 5261, 5318, 5374]}, {"subject_area"=>"/Biology and life sciences/Immunology", "average_usage"=>[285, 598, 757, 913, 1055, 1163, 1259, 1351, 1443, 1527, 1591, 1650, 1720, 1787, 1856, 1918, 1966, 2017, 2087, 2137, 2201, 2254, 2314, 2370, 2437, 2490, 2549, 2602, 2665, 2701, 2754, 2801, 2844, 2894, 2939, 3003, 3050, 3112, 3157, 3196, 3242, 3284, 3335, 3388, 3440, 3490, 3533, 3577, 3630, 3678, 3724, 3773, 3827, 3881, 3931, 3983, 4041, 4096, 4150, 4223, 4269, 4299, 4346, 4400, 4478, 4525, 4602, 4652, 4721, 4783, 4833, 4872, 4908]}, {"subject_area"=>"/Physical sciences", "average_usage"=>[316, 648, 828, 974, 1107, 1224, 1324, 1403, 1481, 1567, 1645, 1736, 1798, 1846, 1908, 1967, 2031, 2088, 2149, 2201, 2260, 2305, 2376, 2434, 2491, 2538, 2598, 2657, 2710, 2757, 2815, 2860, 2907, 2972, 3022, 3070, 3113, 3157, 3213, 3267, 3326, 3388, 3427, 3493, 3550, 3612, 3666, 3715, 3775, 3836, 3900, 3978, 4042, 4105, 4156, 4235, 4314, 4370, 4441, 4511, 4615, 4676, 4744, 4791, 4849, 4915, 4982, 5035, 5099, 5173, 5228, 5303, 5352]}]}
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