Cell Type-Specific Functions of Period Genes Revealed by Novel Adipocyte and Hepatocyte Circadian Clock Models
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{"title"=>"Cell Type-Specific Functions of Period Genes Revealed by Novel Adipocyte and Hepatocyte Circadian Clock Models", "type"=>"journal", "authors"=>[{"first_name"=>"Chidambaram", "last_name"=>"Ramanathan", "scopus_author_id"=>"12782061400"}, {"first_name"=>"Haiyan", "last_name"=>"Xu", "scopus_author_id"=>"56608259500"}, {"first_name"=>"Sanjoy K.", "last_name"=>"Khan", "scopus_author_id"=>"50461653700"}, {"first_name"=>"Yang", "last_name"=>"Shen", "scopus_author_id"=>"56177733400"}, {"first_name"=>"Paula J.", "last_name"=>"Gitis", "scopus_author_id"=>"55151180100"}, {"first_name"=>"David K.", "last_name"=>"Welsh", "scopus_author_id"=>"7103184617"}, {"first_name"=>"John B.", "last_name"=>"Hogenesch", "scopus_author_id"=>"7003698468"}, {"first_name"=>"Andrew C.", "last_name"=>"Liu", "scopus_author_id"=>"7402583346"}], "year"=>2014, "source"=>"PLoS Genetics", "identifiers"=>{"pui"=>"373162848", "sgr"=>"84901345617", "issn"=>"15537404", "pmid"=>"24699442", "scopus"=>"2-s2.0-84901345617", "doi"=>"10.1371/journal.pgen.1004244", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)"}, "id"=>"44a28693-5b5b-3254-a968-a591ce80a98d", "abstract"=>"In animals, circadian rhythms in physiology and behavior result from coherent rhythmic interactions between clocks in the brain and those throughout the body. Despite the many tissue specific clocks, most understanding of the molecular core clock mechanism comes from studies of the suprachiasmatic nuclei (SCN) of the hypothalamus and a few other cell types. Here we report establishment and genetic characterization of three cell-autonomous mouse clock models: 3T3 fibroblasts, 3T3-L1 adipocytes, and MMH-D3 hepatocytes. Each model is genetically tractable and has an integrated luciferase reporter that allows for longitudinal luminescence recording of rhythmic clock gene expression using an inexpensive off-the-shelf microplate reader. To test these cellular models, we generated a library of short hairpin RNAs (shRNAs) against a panel of known clock genes and evaluated their impact on circadian rhythms. Knockdown of Bmal1, Clock, Cry1, and Cry2 each resulted in similar phenotypes in all three models, consistent with previous studies. However, we observed cell type-specific knockdown phenotypes for the Period and Rev-Erb families of clock genes. In particular, Per1 and Per2, which have strong behavioral effects in knockout mice, appear to play different roles in regulating period length and amplitude in these peripheral systems. Per3, which has relatively modest behavioral effects in knockout mice, substantially affects period length in the three cellular models and in dissociated SCN neurons. In summary, this study establishes new cell-autonomous clock models that are of particular relevance to metabolism and suitable for screening for clock modifiers, and reveals previously under-appreciated cell type-specific functions of clock genes.", "link"=>"http://www.mendeley.com/research/cell-typespecific-functions-period-genes-revealed-novel-adipocyte-hepatocyte-circadian-clock-models", "reader_count"=>85, "reader_count_by_academic_status"=>{"Unspecified"=>4, "Professor > Associate Professor"=>9, "Librarian"=>1, "Student > Doctoral Student"=>6, "Researcher"=>10, "Student > Ph. D. Student"=>20, "Student > Postgraduate"=>3, "Student > Master"=>16, "Other"=>1, "Student > Bachelor"=>8, "Professor"=>7}, "reader_count_by_user_role"=>{"Unspecified"=>4, "Professor > Associate Professor"=>9, "Librarian"=>1, "Student > Doctoral Student"=>6, "Researcher"=>10, "Student > Ph. D. Student"=>20, "Student > Postgraduate"=>3, "Student > Master"=>16, "Other"=>1, "Student > Bachelor"=>8, "Professor"=>7}, "reader_count_by_subject_area"=>{"Unspecified"=>7, "Engineering"=>3, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>17, "Medicine and Dentistry"=>5, "Agricultural and Biological Sciences"=>43, "Neuroscience"=>3, "Arts and Humanities"=>1, "Chemistry"=>1, "Psychology"=>1, "Computer Science"=>1, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>3}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>5}, "Neuroscience"=>{"Neuroscience"=>3}, "Chemistry"=>{"Chemistry"=>1}, "Psychology"=>{"Psychology"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>43}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>17}, "Unspecified"=>{"Unspecified"=>7}, "Environmental Science"=>{"Environmental Science"=>1}, "Arts and Humanities"=>{"Arts and Humanities"=>1}}, "reader_count_by_country"=>{"Sweden"=>1, "Czech Republic"=>1, "United States"=>3, "United Kingdom"=>1, "France"=>2, "Germany"=>1}, "group_count"=>2}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1449485"], "description"=>"<p>Bioluminescence expression patterns upon KD of <i>Nr1d1</i> and <i>Nr1d2</i> (A) and <i>E4bp4</i> (B) in all three cell types. See <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004244#pgen-1004244-g002\" target=\"_blank\">Figure 2</a> for details. Note that, compared to the more prominent role of <i>Nr1d1</i> in clock function previously found in U2OS cells or mouse behavioral rhythms <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004244#pgen.1004244-Cho1\" target=\"_blank\">[18]</a>, <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004244#pgen.1004244-Baggs1\" target=\"_blank\">[27]</a>, <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004244#pgen.1004244-Preitner1\" target=\"_blank\">[49]</a>, <i>Nr1d2</i> plays a more prominent role in all three cells. <i>E4bp4</i> KD caused period length and/or amplitude phenotypes depending cell type.</p>", "links"=>[], "tags"=>["cell biology", "Cellular types", "Molecular cell biology", "Computational biology", "Gene regulatory networks", "genetics", "Gene function", "Molecular genetics", "type-specific", "circadian"], "article_id"=>986688, "categories"=>["Biological Sciences"], "users"=>["Chidambaram Ramanathan", "Haiyan Xu", "Sanjoy K. Khan", "Yang Shen", "Paula J. Gitis", "David K. Welsh", "John B. Hogenesch", "Andrew C. Liu"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004244.g003", "stats"=>{"downloads"=>0, "page_views"=>40, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Knockdowns_of_Nr1d1_Nr1d2_and_E4bp4_lead_to_cell_type_specific_circadian_phenotypes_/986688", "title"=>"Knockdowns of <i>Nr1d1</i>, <i>Nr1d2</i>, and <i>E4bp4</i> lead to cell type-specific circadian phenotypes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-03 04:09:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/1449488"], "description"=>"<p>(A) Representative bioluminescence expression patterns recorded on LumiCycle upon knockdowns of <i>Per1</i>, <i>Per2</i>, <i>Per3</i> (single KD); <i>Per1</i>/<i>Per2</i>, <i>Per1</i>/<i>Per3</i>, <i>Per2</i>/<i>Per3</i> (double KD); and <i>Per1</i>/<i>Per2</i>/<i>Per3</i> (triple KD) in MMH-D3 hepatocytes. sh62, sh67 and sh74 were used to knock down <i>Per1</i>, <i>Per2</i> and <i>Per3</i>, respectively. All single KDs led to short periods in all three cell types, consistent with Synergy assays. <i>Per1</i>/<i>Per2</i> double and <i>Per1</i>/<i>Per2</i>/<i>Per3</i> triple KDs caused arrhythmicity. All other double composite KDs caused short period phenotype. (B) Summary of period length phenotypes. Data are mean ± SD (n = 3 independent samples/wells from one experiment). NS, non-specific shRNA. Compared to NS controls, significant difference in period length was detected (NS vs. <i>Per1</i> KD, t-test, p<0.001; NS vs. <i>Per2</i> KD, t-test, p<0.001; NS vs. <i>Per3</i> KD, t-test, p<0.001; NS vs. <i>Per1</i>/<i>Per3</i> KD, t-test, p<0.001; NS vs. <i>Per2</i>/<i>Per3</i> KD, t-test, p<0.001). (C) qPCR analysis of clock gene expression upon <i>Per</i> KD in non-synchronized MMH-D3 cells. Values for each gene are expressed as percentage of gene expression in NS control cells. Data represent two samples/wells from one experiment.</p>", "links"=>[], "tags"=>["cell biology", "Cellular types", "Molecular cell biology", "Computational biology", "Gene regulatory networks", "genetics", "Gene function", "Molecular genetics", "composite", "knockdown", "mmh-d3"], "article_id"=>986691, "categories"=>["Biological Sciences"], "users"=>["Chidambaram Ramanathan", "Haiyan Xu", "Sanjoy K. Khan", "Yang Shen", "Paula J. Gitis", "David K. Welsh", "John B. Hogenesch", "Andrew C. Liu"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004244.g005", "stats"=>{"downloads"=>3, "page_views"=>30, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_shRNA_mediated_single_and_composite_knockdown_effects_of_Per1_Per2_and_Per3_in_MMH_D3_hepatocytes_/986691", "title"=>"shRNA-mediated single and composite knockdown effects of <i>Per1</i>, <i>Per2</i> and <i>Per3</i> in MMH-D3 hepatocytes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-03 04:09:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/1449473"], "description"=>"<p>(A) Representative bioluminescence rhythms of reporter cells recorded in a LumiCycle luminometer on 35 mm dishes. Reporter cells were generated via lentiviral infection of either <i>Per2</i>-d<i>Luc</i> or <i>Bmal1</i>-d<i>Luc</i> luciferase reporter, and infected cell populations were recorded in a LumiCycle. Baseline-subtracted bioluminescence data of both reporter lines are plotted together to show the expected, approximately anti-phasic reporter expression for each cell type. (B) Representative bioluminescence rhythms of homogenous clonal cell lines recorded in a Synergy microplate reader on 96 well plates. Baseline-subtracted bioluminescence data of selected clonal lines representing both reporter types are plotted together to show anti-phasic reporter expression for each cell type. High reproducibility is illustrated by showing overlapping traces from 24 of the 96 wells for each reporter. The period lengths are highly consistent (mean ± SD, n = 24 for each line): 3T3 <i>Per2</i>-d<i>Luc</i>, 25.62 hr±0.21; 3T3 <i>Bmal1</i>-d<i>Luc</i>, 26.72 hr±0.31; 3T3-L1 <i>Per2</i>-d<i>Luc</i>, 24.60 hr±0.32; 3T3-L1 <i>Bmal1</i>-d<i>Luc</i>, 25.01 hr±0.19; MMH-D3 <i>Per2</i>-d<i>Luc</i>, 24.49 hr±0.18; MMH-D3 <i>Bmal1</i>-d<i>Luc</i>, 25.33 hr±0.13.</p>", "links"=>[], "tags"=>["cell biology", "Cellular types", "Molecular cell biology", "Computational biology", "Gene regulatory networks", "genetics", "Gene function", "Molecular genetics", "hepatocytes", "bioluminescence"], "article_id"=>986676, "categories"=>["Biological Sciences"], "users"=>["Chidambaram Ramanathan", "Haiyan Xu", "Sanjoy K. Khan", "Yang Shen", "Paula J. Gitis", "David K. Welsh", "John B. Hogenesch", "Andrew C. Liu"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004244.g001", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Fibroblasts_adipocytes_and_hepatocytes_display_bioluminescence_rhythms_/986676", "title"=>"Fibroblasts, adipocytes, and hepatocytes display bioluminescence rhythms.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-03 04:09:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/1449487"], "description"=>"<p>Bioluminescence expression patterns upon KD of <i>Per1</i> (A), <i>Per2</i> (B), and <i>Per3</i> (C) in all three cell types. See <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004244#pgen-1004244-g002\" target=\"_blank\">Figure 2</a> for details. Whereas <i>Per3</i> KD led to short periods in all three cell types, <i>Per1</i> and <i>Per2</i> KDs caused different clock phenotypes depending on cell type. (D) Summary of period length phenotypes. Data are mean ± SD (n = 4 independent experiments for 3T3 cells; n = 3 samples/wells of one experiment for 3T3-L1 and MMH-D3 cells). NS, non-specific shRNA. Compared to NS controls, significant difference in period length was detected in the following KDs: NS vs. <i>Per1</i> KD in MMH-D3, t-test, p<0.001; NS vs. <i>Per2</i> KD in 3T3, t-test, p = 0.013; NS vs. <i>Per2</i> KD in MMH-D3, t-test, p<0.001; NS vs. <i>Per3</i> KD in 3T3, t-test, p<0.001; NS vs. <i>Per3</i> KD in 3T3-L1, t-test, p = 0.003; NS vs. <i>Per3</i> KD in MMH-D3, t-test, p<0.001). *p<0.01; ** p<0.001. (E) <i>Per3</i> deletion led to short period length defects in SCN explants (left) and even stronger defects in dissociated SCN neurons (right). <i>Per3<sup>−/−</sup></i> SCN explants show a slightly shorter period than WT (mean ± SEM: WT, 24.4 hr±0.17, n = 5; <i>Per3<sup>−/−</sup></i>, 23.78 hr±0.18, n = 5). The mean period of rhythms in <i>Per3<sup>−/−</sup></i> neurons was substantially shorter than in WT cells (mean ± SEM: WT, 27.23 hr±0.24, n = 106; <i>Per3<sup>−/−</sup></i>, 25.58 hr±0.12, n = 157; t-test, p<10E-10; ** p<0.001).</p>", "links"=>[], "tags"=>["cell biology", "Cellular types", "Molecular cell biology", "Computational biology", "Gene regulatory networks", "genetics", "Gene function", "Molecular genetics", "knockdowns", "type-specific", "circadian"], "article_id"=>986690, "categories"=>["Biological Sciences"], "users"=>["Chidambaram Ramanathan", "Haiyan Xu", "Sanjoy K. Khan", "Yang Shen", "Paula J. Gitis", "David K. Welsh", "John B. Hogenesch", "Andrew C. Liu"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004244.g004", "stats"=>{"downloads"=>0, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_shRNA_mediated_knockdowns_of_Per1_Per2_and_Per3_lead_to_cell_type_specific_circadian_phenotypes_/986690", "title"=>"shRNA-mediated knockdowns of <i>Per1</i>, <i>Per2</i> and <i>Per3</i> lead to cell type-specific circadian phenotypes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-03 04:09:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/1449500", "https://ndownloader.figshare.com/files/1449501", "https://ndownloader.figshare.com/files/1449502", "https://ndownloader.figshare.com/files/1449503", "https://ndownloader.figshare.com/files/1449504", "https://ndownloader.figshare.com/files/1449505", "https://ndownloader.figshare.com/files/1449506", "https://ndownloader.figshare.com/files/1449507", "https://ndownloader.figshare.com/files/1449508", "https://ndownloader.figshare.com/files/1449510", "https://ndownloader.figshare.com/files/1449511", "https://ndownloader.figshare.com/files/1449512"], "description"=>"<div><p>In animals, circadian rhythms in physiology and behavior result from coherent rhythmic interactions between clocks in the brain and those throughout the body. Despite the many tissue specific clocks, most understanding of the molecular core clock mechanism comes from studies of the suprachiasmatic nuclei (SCN) of the hypothalamus and a few other cell types. Here we report establishment and genetic characterization of three cell-autonomous mouse clock models: 3T3 fibroblasts, 3T3-L1 adipocytes, and MMH-D3 hepatocytes. Each model is genetically tractable and has an integrated luciferase reporter that allows for longitudinal luminescence recording of rhythmic clock gene expression using an inexpensive off-the-shelf microplate reader. To test these cellular models, we generated a library of short hairpin RNAs (shRNAs) against a panel of known clock genes and evaluated their impact on circadian rhythms. Knockdown of <i>Bmal1</i>, <i>Clock</i>, <i>Cry1</i>, and <i>Cry2</i> each resulted in similar phenotypes in all three models, consistent with previous studies. However, we observed cell type-specific knockdown phenotypes for the <i>Period</i> and <i>Rev-Erb</i> families of clock genes. In particular, <i>Per1</i> and <i>Per2</i>, which have strong behavioral effects in knockout mice, appear to play different roles in regulating period length and amplitude in these peripheral systems. <i>Per3</i>, which has relatively modest behavioral effects in knockout mice, substantially affects period length in the three cellular models and in dissociated SCN neurons. In summary, this study establishes new cell-autonomous clock models that are of particular relevance to metabolism and suitable for screening for clock modifiers, and reveals previously under-appreciated cell type-specific functions of clock genes.</p></div>", "links"=>[], "tags"=>["cell biology", "Cellular types", "Molecular cell biology", "Computational biology", "Gene regulatory networks", "genetics", "Gene function", "Molecular genetics", "type-specific", "functions", "genes", "revealed", "adipocyte", "hepatocyte", "circadian"], "article_id"=>986703, "categories"=>["Biological Sciences"], "users"=>["Chidambaram Ramanathan", "Haiyan Xu", "Sanjoy K. Khan", "Yang Shen", "Paula J. Gitis", "David K. Welsh", "John B. Hogenesch", "Andrew C. Liu"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004244.s001", "https://dx.doi.org/10.1371/journal.pgen.1004244.s002", "https://dx.doi.org/10.1371/journal.pgen.1004244.s003", "https://dx.doi.org/10.1371/journal.pgen.1004244.s004", "https://dx.doi.org/10.1371/journal.pgen.1004244.s005", "https://dx.doi.org/10.1371/journal.pgen.1004244.s006", "https://dx.doi.org/10.1371/journal.pgen.1004244.s007", "https://dx.doi.org/10.1371/journal.pgen.1004244.s008", "https://dx.doi.org/10.1371/journal.pgen.1004244.s009", "https://dx.doi.org/10.1371/journal.pgen.1004244.s010", "https://dx.doi.org/10.1371/journal.pgen.1004244.s011", "https://dx.doi.org/10.1371/journal.pgen.1004244.s012"], "stats"=>{"downloads"=>24, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Cell_Type_Specific_Functions_of_Period_Genes_Revealed_by_Novel_Adipocyte_and_Hepatocyte_Circadian_Clock_Models/986703", "title"=>"Cell Type-Specific Functions of <i>Period</i> Genes Revealed by Novel Adipocyte and Hepatocyte Circadian Clock Models", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-04-03 04:09:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/1449481"], "description"=>"<p>Bioluminescence expression patterns upon KD of <i>Bmal1</i> or <i>Clock</i> (A), <i>Cry1</i> or <i>Cry2</i> (B), and <i>Fbxl3</i> (C) in all three cell types. For clock phenotyping, both reporters were used for each cell line and phenotypes were independent of the reporter used. For phenotyping, we selected 3T3 cells expressing the <i>Bmal1</i>-d<i>Luc</i> reporter, and 3T3-L1 and MMH-D3 cells expressing the <i>Per2</i>-d<i>Luc</i> reporter. Cells were infected with specific lentiviral shRNAs as indicated. Real-time bioluminescence expression was recorded by Synergy microplate reader as in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004244#pgen-1004244-g001\" target=\"_blank\">Figure 1</a>. Out of the 6 shRNAs tested, two validated shRNAs (orange and green) are shown. NS, non-specific shRNA as control (black). While KD of <i>Bmal1</i> or <i>Clock</i> resulted in low amplitude, rapid damping or arrhythmicity, <i>Fbxl3</i> KD led to long period and low amplitude in 3T3, long period in 3T3-L1, and low amplitude and rapid damping in MMH-D3 cells. <i>Cry1</i> KD caused rapid damping or low amplitude, and <i>Cry2</i> KD lengthened period and increased rhythm amplitude. Bioluminescence data are representative of four independent experiments for 3T3 and 3T3-L1 cells, and three independent experiments for MMH-D3 cells. Knockdown of endogenous mRNA expression in non-synchronized cells was determined by qPCR (insert). Values for each gene are expressed as percentage of gene expression in NS control cells. qPCR data are mean ± SD (two samples/wells from one experiment).</p>", "links"=>[], "tags"=>["cell biology", "Cellular types", "Molecular cell biology", "Computational biology", "Gene regulatory networks", "genetics", "Gene function", "Molecular genetics", "type-ubiquitous", "circadian"], "article_id"=>986684, "categories"=>["Biological Sciences"], "users"=>["Chidambaram Ramanathan", "Haiyan Xu", "Sanjoy K. Khan", "Yang Shen", "Paula J. Gitis", "David K. Welsh", "John B. Hogenesch", "Andrew C. Liu"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004244.g002", "stats"=>{"downloads"=>1, "page_views"=>47, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Knockdowns_of_Bmal1_Clock_Cry1_Cry2_and_Fbxl3_lead_to_cell_type_ubiquitous_circadian_phenotypes_/986684", "title"=>"Knockdowns of <i>Bmal1</i>, <i>Clock</i>, <i>Cry1</i>, <i>Cry2</i>, and <i>Fbxl3</i> lead to cell type-ubiquitous circadian phenotypes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-03 04:09:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/1449489"], "description"=>"<p>Notes:</p><p>1) Knockdown phenotypes in 3T3 fibroblasts, 3T3-L1 adipocytes, and MMH-D3 hepatocytes are from this study, and those in U2OS osteosarcoma cells are from <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004244#pgen.1004244-Baggs1\" target=\"_blank\">[27]</a>, <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004244#pgen.1004244-Zhang1\" target=\"_blank\">[31]</a>.</p><p>2) Detailed circadian parameter analyses and phenotypes in 3T3, 3T3-L1 and MMH-D3 cells are presented in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004244#pgen.1004244.s007\" target=\"_blank\">Tables S1</a>, <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004244#pgen.1004244.s008\" target=\"_blank\">S2</a>, <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004244#pgen.1004244.s009\" target=\"_blank\">S3</a>.</p><p>3) Phenotypes: WT, wild type; short, shorter period length than WT; long, longer period length than WT; LA, rhythmic but low amplitude; HA, rhythmic but high amplitude; RD, rapid damping (i.e., rapid decline in amplitude over time) and only transiently rhythmic; AR, arrhythmic.</p>", "links"=>[], "tags"=>["cell biology", "Cellular types", "Molecular cell biology", "Computational biology", "Gene regulatory networks", "genetics", "Gene function", "Molecular genetics", "knockdown"], "article_id"=>986692, "categories"=>["Biological Sciences"], "users"=>["Chidambaram Ramanathan", "Haiyan Xu", "Sanjoy K. Khan", "Yang Shen", "Paula J. Gitis", "David K. Welsh", "John B. Hogenesch", "Andrew C. Liu"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004244.t001", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Summary_of_knockdown_phenotypes_/986692", "title"=>"Summary of knockdown phenotypes.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-04-03 04:09:58"}

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Relative Metric

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