Global Mapping of Cell Type–Specific Open Chromatin by FAIRE-seq Reveals the Regulatory Role of the NFI Family in Adipocyte Differentiation
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{"title"=>"Global mapping of cell type-specific open chromatin by FAIRE-seq reveals the regulatory role of the NFI family in adipocyte differentiation", "type"=>"journal", "authors"=>[{"first_name"=>"Hironori", "last_name"=>"Waki", "scopus_author_id"=>"7006469930"}, {"first_name"=>"Masahiro", "last_name"=>"Nakamura", "scopus_author_id"=>"56340319200"}, {"first_name"=>"Toshimasa", "last_name"=>"Yamauchi", "scopus_author_id"=>"35370926900"}, {"first_name"=>"Ken ichi", "last_name"=>"Wakabayashi", "scopus_author_id"=>"7402088062"}, {"first_name"=>"Jing", "last_name"=>"Yu", "scopus_author_id"=>"57195295655"}, {"first_name"=>"Lisa", "last_name"=>"Hirose-Yotsuya", "scopus_author_id"=>"53981189100"}, {"first_name"=>"Kazumi", "last_name"=>"Take", "scopus_author_id"=>"57197984380"}, {"first_name"=>"Wei", "last_name"=>"Sun", "scopus_author_id"=>"55574205597"}, {"first_name"=>"Masato", "last_name"=>"Iwabu", "scopus_author_id"=>"16031322300"}, {"first_name"=>"Miki", "last_name"=>"Okada-Iwabu", "scopus_author_id"=>"6505734829"}, {"first_name"=>"Takanori", "last_name"=>"Fujita", "scopus_author_id"=>"7405808499"}, {"first_name"=>"Tomohisa", "last_name"=>"Aoyama", "scopus_author_id"=>"36787296400"}, {"first_name"=>"Shuichi", "last_name"=>"Tsutsumi", "scopus_author_id"=>"35408216500"}, {"first_name"=>"Kohjiro", "last_name"=>"Ueki", "scopus_author_id"=>"35377456200"}, {"first_name"=>"Tatsuhiko", "last_name"=>"Kodama", "scopus_author_id"=>"56801297000"}, {"first_name"=>"Juro", "last_name"=>"Sakai", "scopus_author_id"=>"7201954359"}, {"first_name"=>"Hiroyuki", "last_name"=>"Aburatani", "scopus_author_id"=>"7005377301"}, {"first_name"=>"Takashi", "last_name"=>"Kadowaki", "scopus_author_id"=>"55460247700"}], "year"=>2011, "source"=>"PLoS Genetics", "identifiers"=>{"scopus"=>"2-s2.0-80055081913", "sgr"=>"80055081913", "issn"=>"15537390", "doi"=>"10.1371/journal.pgen.1002311", "pmid"=>"22028663", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)", "pui"=>"362834381"}, "id"=>"b57a5897-0ff7-3c36-89e7-19c9a33ec60d", "abstract"=>"Identification of regulatory elements within the genome is crucial for understanding the mechanisms that govern cell type-specific gene expression. We generated genome-wide maps of open chromatin sites in 3T3-L1 adipocytes (on day 0 and day 8 of differentiation) and NIH-3T3 fibroblasts using formaldehyde-assisted isolation of regulatory elements coupled with high-throughput sequencing (FAIRE-seq). FAIRE peaks at the promoter were associated with active transcription and histone modifications of H3K4me3 and H3K27ac. Non-promoter FAIRE peaks were characterized by H3K4me1+/me3-, the signature of enhancers, and were largely located in distal regions. The non-promoter FAIRE peaks showed dynamic change during differentiation, while the promoter FAIRE peaks were relatively constant. Functionally, the adipocyte- and preadipocyte-specific non-promoter FAIRE peaks were, respectively, associated with genes up-regulated and down-regulated by differentiation. Genes highly up-regulated during differentiation were associated with multiple clustered adipocyte-specific FAIRE peaks. Among the adipocyte-specific FAIRE peaks, 45.3% and 11.7% overlapped binding sites for, respectively, PPARγ and C/EBPα, the master regulators of adipocyte differentiation. Computational motif analyses of the adipocyte-specific FAIRE peaks revealed enrichment of a binding motif for nuclear family I (NFI) transcription factors. Indeed, ChIP assay showed that NFI occupy the adipocyte-specific FAIRE peaks and/or the PPARγ binding sites near PPARγ, C/EBPα, and aP2 genes. Overexpression of NFIA in 3T3-L1 cells resulted in robust induction of these genes and lipid droplet formation without differentiation stimulus. Overexpression of dominant-negative NFIA or siRNA-mediated knockdown of NFIA or NFIB significantly suppressed both induction of genes and lipid accumulation during differentiation, suggesting a physiological function of these factors in the adipogenic program. Together, our study demonstrates the utility of FAIRE-seq in providing a global view of cell type-specific regulatory elements in the genome and in identifying transcriptional regulators of adipocyte differentiation.", "link"=>"http://www.mendeley.com/research/global-mapping-cell-typespecific-open-chromatin-faireseq-reveals-regulatory-role-nfi-family-adipocyt", "reader_count"=>171, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>13, "Researcher"=>60, "Student > Doctoral Student"=>11, "Student > Ph. D. Student"=>51, "Student > Postgraduate"=>5, "Student > Master"=>12, "Other"=>1, "Student > Bachelor"=>6, "Professor"=>9}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>13, "Researcher"=>60, "Student > Doctoral Student"=>11, "Student > Ph. D. Student"=>51, "Student > Postgraduate"=>5, "Student > Master"=>12, "Other"=>1, "Student > Bachelor"=>6, "Professor"=>9}, "reader_count_by_subject_area"=>{"Unspecified"=>8, "Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>21, "Mathematics"=>1, "Agricultural and Biological Sciences"=>110, "Medicine and Dentistry"=>20, "Neuroscience"=>2, "Physics and Astronomy"=>2, "Chemistry"=>1, "Social Sciences"=>1, "Computer Science"=>2, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>20}, "Neuroscience"=>{"Neuroscience"=>2}, "Chemistry"=>{"Chemistry"=>1}, "Social Sciences"=>{"Social Sciences"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>2}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>110}, "Computer Science"=>{"Computer Science"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>21}, "Mathematics"=>{"Mathematics"=>1}, "Unspecified"=>{"Unspecified"=>8}}, "reader_count_by_country"=>{"United States"=>8, "Japan"=>2, "United Kingdom"=>1, "Portugal"=>1, "India"=>1, "Canada"=>1, "Czech Republic"=>1, "Norway"=>1, "Luxembourg"=>1, "Mexico"=>1, "Israel"=>1, "France"=>3, "Germany"=>1}, "group_count"=>5}

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  • {"files"=>["https://ndownloader.figshare.com/files/720991"], "description"=>"<p>(A) Venn diagrams comparing the FAIRE peaks among 3T3-L1 (day 0), 3T3-L1 (day 8) and NIH-3T3 at promoter (+/−500 bp from RefSeq TSS) and non-promoter regions. The promoter FAIRE peaks were relatively constant among the three cell groups while the non-promoter FAIRE peaks were highly variable. (B) The FAIRE peaks in 3T3-L1 (day 0 or day 8) were divided into tertiles by peak height and adipocyte- (red boxes) and preadipocyte-specific (green boxes) FAIRE peaks, and were defined as indicated. (C) A heat map showing enrichment of the adipocyte- and preadipocyte-specific FAIRE peaks in the vicinity (+/−25 kb from TSS) of genes up-regulated or down-regulated during differentiation. The horizontal bars in the two right panels indicate each gene with Ad or pAd FAIRE peaks in the vicinity (+/−25 kb from TSS). (D) Fractions of genes that were up-regulated (left) or down-regulated (right) more than two-fold during differentiation among genes that had the indicated number of adipocyte- (red), preadipocyte-specific (green) or invariant (blue) FAIRE peaks. (E) The number of the adipocyte- (red), preadipocyte-specific (green) or invariant (blue) FAIRE peaks associated with genes that were stratified by the ratio of the expression levels between preadipocytes and adipocytes. Each FAIRE peak was defined as associated with the nearest gene in analyses (D) and (E). (F) Ontology analysis by DAVID of genes associated (+/−25 kb from TSS) with adipocyte-specific FAIRE peaks <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002311#pgen.1002311-Barak1\" target=\"_blank\">[13]</a>. (G) Venn diagrams showing the numbers and overlap of the binding sites for PPARγ and RXRα in 3T3-L1, day 0 and day 8. (H, I) Fractions of the non-promoter FAIRE peaks that overlap PPARγ binding sites (day 8) (H) or C/EBPα binding sites (Schmidt et al., GSE27450 <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002311#pgen.1002311-Schmidt2\" target=\"_blank\">[86]</a>) (I). PPARγ and C/EBPα represented 45.3% and 11.7% of the adipocyte-specific FAIRE peaks (average of red bars).</p>", "links"=>[], "tags"=>["differentiation-dependent", "faire"], "article_id"=>391328, "categories"=>["Chemistry", "Biochemistry", "Developmental Biology", "Molecular Biology", "Cell Biology", "Genetics"], "users"=>["Hironori Waki", "Masahiro Nakamura", "Toshimasa Yamauchi", "Ken-ichi Wakabayashi", "Jing Yu", "Lisa Hirose-Yotsuya", "Kazumi Take", "Wei Sun", "Masato Iwabu", "Miki Okada-Iwabu", "Takanori Fujita", "Tomohisa Aoyama", "Shuichi Tsutsumi", "Kohjiro Ueki", "Tatsuhiko Kodama", "Juro Sakai", "Hiroyuki Aburatani", "Takashi Kadowaki"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002311.g002", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cell_type_8211_and_differentiation_dependent_FAIRE_peaks_/391328", "title"=>"Cell type– and differentiation-dependent FAIRE peaks.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-20 00:22:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/721120"], "description"=>"<p>The PPARγ binding sites in the <i>Adipor2</i> gene locus (<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002311#pgen.1002311.s002\" target=\"_blank\">Figure S2B</a>, arrow heads) were analyzed. (A) Putative DR-1 motifs (PPAR response elements or PPREs) in the regions. ARE6 and ARE7 in the −5.4 kb promoter upstream of <i>Fabp4</i>(aP2) were previously identified PPREs <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002311#pgen.1002311-Graves2\" target=\"_blank\">[87]</a>. (B) Gel shift assay showing binding of the PPARγ/RXR heterodimer to the motifs. An arrow indicates the PPARγ/RXRα heterodimer bound by radiolabeled probe. Competition by cold oligos showed the specificity of the binding. (C) Luciferase reporter assay in HEK293T cells. Most of the motifs inserted into reporter vectors with the tk minimal promoter responded to over-expressed PPARγ/RXRα and stimulation with its synthetic ligand, rosiglitazone. The −5.4 kb promoter of PPARγ target gene <i>Fabp4</i> (aP2) <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002311#pgen.1002311-Waki2\" target=\"_blank\">[84]</a> was included as a positive control.</p>", "links"=>[], "tags"=>["elements", "intron"], "article_id"=>391454, "categories"=>["Chemistry", "Biochemistry", "Developmental Biology", "Molecular Biology", "Cell Biology", "Genetics"], "users"=>["Hironori Waki", "Masahiro Nakamura", "Toshimasa Yamauchi", "Ken-ichi Wakabayashi", "Jing Yu", "Lisa Hirose-Yotsuya", "Kazumi Take", "Wei Sun", "Masato Iwabu", "Miki Okada-Iwabu", "Takanori Fujita", "Tomohisa Aoyama", "Shuichi Tsutsumi", "Kohjiro Ueki", "Tatsuhiko Kodama", "Juro Sakai", "Hiroyuki Aburatani", "Takashi Kadowaki"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002311.g003", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Identification_of_functional_regulatory_elements_in_the_intron_1_of_Adipor2_/391454", "title"=>"Identification of functional regulatory elements in the intron 1 of <i>Adipor2</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-20 00:24:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/721489"], "description"=>"<p>(A) Transcriptional regulation of NFI transcription factors during adipocyte differentiation (3T3-F442A). (B) Tissue distribution of the NFI family genes. Expression levels relative to 36B4 in various tissues were determined by qPCR. (C, D) Effects of siRNA-mediated knockdown of NFIA and NFIB on adipogenic gene expression (C) and lipid accumulation in 3T3-L1 adipocytes judged by oil red O staining (D). Knockdown of either NFIA or NFIB resulted in suppression of the induction of PPARγ, C/EBPα and the PPARγ target gene, aP2, as well as increase in lipid accumulation during adipocyte differentiation.</p>", "links"=>[], "tags"=>["nfib", "regulators", "adipocyte"], "article_id"=>391823, "categories"=>["Chemistry", "Biochemistry", "Developmental Biology", "Molecular Biology", "Cell Biology", "Genetics"], "users"=>["Hironori Waki", "Masahiro Nakamura", "Toshimasa Yamauchi", "Ken-ichi Wakabayashi", "Jing Yu", "Lisa Hirose-Yotsuya", "Kazumi Take", "Wei Sun", "Masato Iwabu", "Miki Okada-Iwabu", "Takanori Fujita", "Tomohisa Aoyama", "Shuichi Tsutsumi", "Kohjiro Ueki", "Tatsuhiko Kodama", "Juro Sakai", "Hiroyuki Aburatani", "Takashi Kadowaki"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002311.g006", "stats"=>{"downloads"=>1, "page_views"=>32, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_NFIA_and_NFIB_are_novel_regulators_of_adipocyte_differentiation_/391823", "title"=>"NFIA and NFIB are novel regulators of adipocyte differentiation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-20 00:30:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/721362"], "description"=>"<p>Enrichment analysis of the adipocyte- (left) and the preadipocyte-specific (right) FAIRE peaks for known motifs in the TRANSFAC database (Release 2010.4) performed by using AME in the MEME suite. After removing repeat regions with RepeatMasker <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002311#pgen.1002311-Chen1\" target=\"_blank\">[83]</a>, DNA sequences from the center 150 bp regions of the top 2,000 cell type–specific FAIRE peaks were analyzed (p-value report threshold : 0.05). Motif enrichment ratios (Ad/pAd FAIRE) for motifs in the TRANSFAC database were also determined by a method described in reference <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002311#pgen.1002311-Mikkelsen1\" target=\"_blank\">[28]</a>. Motifs with an enrichment ratio greater than 1.20 (for the adipocyte-specific FAIRE peaks, left) or less than 0.833 (for the preadipocyte-specific FAIRE peaks, right) are shown in the table. See “<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002311#s4\" target=\"_blank\">Materials and Methods</a>” for details.</p>", "links"=>[], "tags"=>["motif", "enrichment", "adipocyte-", "preadipocyte-specific", "faire", "peaks"], "article_id"=>391689, "categories"=>["Chemistry", "Biochemistry", "Developmental Biology", "Molecular Biology", "Cell Biology", "Genetics"], "users"=>["Hironori Waki", "Masahiro Nakamura", "Toshimasa Yamauchi", "Ken-ichi Wakabayashi", "Jing Yu", "Lisa Hirose-Yotsuya", "Kazumi Take", "Wei Sun", "Masato Iwabu", "Miki Okada-Iwabu", "Takanori Fujita", "Tomohisa Aoyama", "Shuichi Tsutsumi", "Kohjiro Ueki", "Tatsuhiko Kodama", "Juro Sakai", "Hiroyuki Aburatani", "Takashi Kadowaki"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002311.g005", "stats"=>{"downloads"=>0, "page_views"=>52, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Known_motif_enrichment_analysis_of_adipocyte_or_preadipocyte_specific_FAIRE_peaks_TRANSFAC_motifs_/391689", "title"=>"Known motif enrichment analysis of adipocyte- or preadipocyte-specific FAIRE peaks (TRANSFAC motifs).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-20 00:28:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/721237"], "description"=>"<p>(A) Histogram showing distribution of intervals (defined as distances to the nearest neighbor sites) among all PPARγ peaks (left) and among the adipocyte-specific FAIRE peaks (right). Note that there was increased occurrence of sites separated by short intervals (indicated by asterisks). See <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002311#pgen.1002311-Stitzel1\" target=\"_blank\">[48]</a> for details of the method. (B) Clustering analysis of the PPARγ binding sites and the adipocyte-specific FAIRE peaks by counting the total number of clusters (defined as more than two peaks) determined for windows with indicated width. The PPARγ binding site or adipocyte-specific FAIRE peak clusters occurred more frequently in the observed data set than in random data with the same number of sites. The difference in the number of clusters was observed at window sizes ranging from 800 bp to 30∼100 kb compared with the random sample. See reference <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002311#pgen.1002311-Crawford1\" target=\"_blank\">[47]</a> for details of the method. (C) Microarray analysis showing both <i>Slc2a4 (Glut4)</i> and <i>Ybx2</i> included in the adipocyte-specific FAIRE peak cluster (<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002311#pgen.1002311.s002\" target=\"_blank\">Figure S2C</a>) co-regulated during differentiation. (D) Neighbors of highly induced genes (>10 fold) were more likely to be up-regulated over three fold (18%, or 112 of 618 neighbors) than the 2,012 of 21,343 total genes (9%) that were up-regulated over three fold (p = 1.26×10<sup>−12</sup>, one-sided Fisher test). Neighbors of randomly selected genes were not significantly up-regulated (p = −0.67, average of 1,000 trials). See reference <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002311#pgen.1002311-Ebisuya1\" target=\"_blank\">[50]</a> for method.</p>", "links"=>[], "tags"=>["analyses", "clustering", "adipocyte-specific", "faire", "peaks", "binding", "sites", "co-regulation", "genes"], "article_id"=>391567, "categories"=>["Chemistry", "Biochemistry", "Developmental Biology", "Molecular Biology", "Cell Biology", "Genetics"], "users"=>["Hironori Waki", "Masahiro Nakamura", "Toshimasa Yamauchi", "Ken-ichi Wakabayashi", "Jing Yu", "Lisa Hirose-Yotsuya", "Kazumi Take", "Wei Sun", "Masato Iwabu", "Miki Okada-Iwabu", "Takanori Fujita", "Tomohisa Aoyama", "Shuichi Tsutsumi", "Kohjiro Ueki", "Tatsuhiko Kodama", "Juro Sakai", "Hiroyuki Aburatani", "Takashi Kadowaki"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002311.g004", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Statistical_analyses_for_clustering_of_adipocyte_specific_FAIRE_peaks_and_PPAR_947_binding_sites_and_co_regulation_of_neighbor_genes_during_adipogenesis_/391567", "title"=>"Statistical analyses for clustering of adipocyte-specific FAIRE peaks and PPARγ binding sites and co-regulation of neighbor genes during adipogenesis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-20 00:26:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/721614"], "description"=>"<p>(A) Expression analysis of overexpressed NFI factors (upper panel) and adipogenic PPARγ, C/EBPα and aP2 (lower panel). Note, overexperssion of NFIA resulted in a robust induction of adipogenic factors. (B) Microscopic pictures of 3T3-L1 cells overexpressing NFI factors at confluence stained by oil red O (day 0). (C) Close examination of NFIA-overexpressing cells revealed formation of lipid droplets without adipogenic stimulus before differentiation. (D) Time course of expression levels of PPARγ, C/EBPα and aP2 during differentiation. Note, the induction of these genes by NFIA overexpression was overtaken by that of control cells, and on day 7, NFIA and NFIB overexpressing cells showed attenuated differentiation. Dominant negative NFIA showed almost complete suppression. (E) Oil red O staining of 3T3-L1 overexpressing NFI factors on day 7.</p>", "links"=>[], "tags"=>["nfia", "3t3-l1"], "article_id"=>391952, "categories"=>["Chemistry", "Biochemistry", "Developmental Biology", "Molecular Biology", "Cell Biology", "Genetics"], "users"=>["Hironori Waki", "Masahiro Nakamura", "Toshimasa Yamauchi", "Ken-ichi Wakabayashi", "Jing Yu", "Lisa Hirose-Yotsuya", "Kazumi Take", "Wei Sun", "Masato Iwabu", "Miki Okada-Iwabu", "Takanori Fujita", "Tomohisa Aoyama", "Shuichi Tsutsumi", "Kohjiro Ueki", "Tatsuhiko Kodama", "Juro Sakai", "Hiroyuki Aburatani", "Takashi Kadowaki"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002311.g007", "stats"=>{"downloads"=>1, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Overexpression_of_NFIA_NFIB_and_dominant_negative_NFIA_in_3T3_L1_cells_/391952", "title"=>"Overexpression of NFIA, NFIB, and dominant negative NFIA in 3T3-L1 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-20 00:32:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/720830"], "description"=>"<p>Open chromatin regions detected by FAIRE-seq were observed in both promoter and non-promoter regions. The non-promoter FAIRE peaks were associated with the binding of PPARγ/RXRα or CTCF, and with the enhancer signature H3K4me1(+)/me3(−) and H3K27ac modification—while the promoter FAIRE peaks were associated with H3K4me3 and H3K27ac modification. Bars below the FAIRE peaks data represent statistically significant FAIRE positive peaks (FDR<10<sup>−4</sup>). Red asterisks indicate the adipocyte-specific FAIRE peaks on day 8 (see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002311#pgen-1002311-g002\" target=\"_blank\">Figure 2B</a> for definition). Multiple adipocyte-specific FAIRE peaks were located within genomic regions near <i>Klf15</i> (A) and <i>Pparg</i> (B) in 3T3-L1 adipocytes. Data marked (†) were obtained from Mikkelsen et al. <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002311#pgen.1002311-Mikkelsen1\" target=\"_blank\">[28]</a> (GSE20752).</p>", "links"=>[], "tags"=>["profiling", "chromatin", "regions", "faire-seq", "3t3-l1", "adipocyte"], "article_id"=>391161, "categories"=>["Chemistry", "Biochemistry", "Developmental Biology", "Molecular Biology", "Cell Biology", "Genetics"], "users"=>["Hironori Waki", "Masahiro Nakamura", "Toshimasa Yamauchi", "Ken-ichi Wakabayashi", "Jing Yu", "Lisa Hirose-Yotsuya", "Kazumi Take", "Wei Sun", "Masato Iwabu", "Miki Okada-Iwabu", "Takanori Fujita", "Tomohisa Aoyama", "Shuichi Tsutsumi", "Kohjiro Ueki", "Tatsuhiko Kodama", "Juro Sakai", "Hiroyuki Aburatani", "Takashi Kadowaki"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002311.g001", "stats"=>{"downloads"=>3, "page_views"=>22, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Genome_wide_profiling_of_open_chromatin_regions_by_FAIRE_seq_in_3T3_L1_adipocyte_differentiation_/391161", "title"=>"Genome-wide profiling of open chromatin regions by FAIRE-seq in 3T3-L1 adipocyte differentiation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-20 00:19:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/365409", "https://ndownloader.figshare.com/files/365460", "https://ndownloader.figshare.com/files/365518", "https://ndownloader.figshare.com/files/365572", "https://ndownloader.figshare.com/files/365614", "https://ndownloader.figshare.com/files/365692", "https://ndownloader.figshare.com/files/365746", "https://ndownloader.figshare.com/files/365789", "https://ndownloader.figshare.com/files/365831", "https://ndownloader.figshare.com/files/365873", "https://ndownloader.figshare.com/files/365934", "https://ndownloader.figshare.com/files/365991"], "description"=>"<div><p>Identification of regulatory elements within the genome is crucial for understanding the mechanisms that govern cell type–specific gene expression. We generated genome-wide maps of open chromatin sites in 3T3-L1 adipocytes (on day 0 and day 8 of differentiation) and NIH-3T3 fibroblasts using formaldehyde-assisted isolation of regulatory elements coupled with high-throughput sequencing (FAIRE-seq). FAIRE peaks at the promoter were associated with active transcription and histone modifications of H3K4me3 and H3K27ac. Non-promoter FAIRE peaks were characterized by H3K4me1+/me3-, the signature of enhancers, and were largely located in distal regions. The non-promoter FAIRE peaks showed dynamic change during differentiation, while the promoter FAIRE peaks were relatively constant. Functionally, the adipocyte- and preadipocyte-specific non-promoter FAIRE peaks were, respectively, associated with genes up-regulated and down-regulated by differentiation. Genes highly up-regulated during differentiation were associated with multiple clustered adipocyte-specific FAIRE peaks. Among the adipocyte-specific FAIRE peaks, 45.3% and 11.7% overlapped binding sites for, respectively, PPARγ and C/EBPα, the master regulators of adipocyte differentiation. Computational motif analyses of the adipocyte-specific FAIRE peaks revealed enrichment of a binding motif for nuclear family I (NFI) transcription factors. Indeed, ChIP assay showed that NFI occupy the adipocyte-specific FAIRE peaks and/or the PPARγ binding sites near PPARγ, C/EBPα, and aP2 genes. Overexpression of NFIA in 3T3-L1 cells resulted in robust induction of these genes and lipid droplet formation without differentiation stimulus. Overexpression of dominant-negative NFIA or siRNA–mediated knockdown of NFIA or NFIB significantly suppressed both induction of genes and lipid accumulation during differentiation, suggesting a physiological function of these factors in the adipogenic program. Together, our study demonstrates the utility of FAIRE-seq in providing a global view of cell type–specific regulatory elements in the genome and in identifying transcriptional regulators of adipocyte differentiation.</p> </div>", "links"=>[], "tags"=>["chromatin", "faire-seq", "reveals", "nfi", "adipocyte", "differentiation"], "article_id"=>132207, "categories"=>["Chemistry", "Biochemistry", "Developmental Biology", "Molecular Biology", "Cell Biology", "Genetics"], "users"=>["Hironori Waki", "Masahiro Nakamura", "Toshimasa Yamauchi", "Ken-ichi Wakabayashi", "Jing Yu", "Lisa Hirose-Yotsuya", "Kazumi Take", "Wei Sun", "Masato Iwabu", "Miki Okada-Iwabu", "Takanori Fujita", "Tomohisa Aoyama", "Shuichi Tsutsumi", "Kohjiro Ueki", "Tatsuhiko Kodama", "Juro Sakai", "Hiroyuki Aburatani", "Takashi Kadowaki"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1002311.s001", "https://dx.doi.org/10.1371/journal.pgen.1002311.s002", "https://dx.doi.org/10.1371/journal.pgen.1002311.s003", "https://dx.doi.org/10.1371/journal.pgen.1002311.s004", "https://dx.doi.org/10.1371/journal.pgen.1002311.s005", "https://dx.doi.org/10.1371/journal.pgen.1002311.s006", "https://dx.doi.org/10.1371/journal.pgen.1002311.s007", "https://dx.doi.org/10.1371/journal.pgen.1002311.s008", "https://dx.doi.org/10.1371/journal.pgen.1002311.s009", "https://dx.doi.org/10.1371/journal.pgen.1002311.s010", "https://dx.doi.org/10.1371/journal.pgen.1002311.s011", "https://dx.doi.org/10.1371/journal.pgen.1002311.s012"], "stats"=>{"downloads"=>1, "page_views"=>26, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Global_Mapping_of_Cell_Type_Specific_Open_Chromatin_by_FAIRE_seq_Reveals_the_Regulatory_Role_of_the_NFI_Family_in_Adipocyte_Differentiation/132207", "title"=>"Global Mapping of Cell Type–Specific Open Chromatin by FAIRE-seq Reveals the Regulatory Role of the NFI Family in Adipocyte Differentiation", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-10-20 00:36:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/721751"], "description"=>"<p>(A) The NFI binding motifs identified in the adipocyte-specific FAIRE peaks and/or the PPARγ binding sites in the vicinity of PPARγ, C/EBPα and aP2. For site numbers, see (B). (B) Genomic location of the regions examined. B1 and B2 are unrelated genomic regions used as background negative controls. (C) ChIP-qPCR analysis using an anti-NFI antibody (H-300). (D) Percent fraction of genes harboring NFI motifs in non-promoter FAIRE peaks (within ±25 kb) were higher when the genes were bound by PPARγ (within ±25 kb) and induced during differentiation.</p>", "links"=>[], "tags"=>["adipocyte-specific", "faire", "peaks", "binding", "sites", "ap2"], "article_id"=>392082, "categories"=>["Chemistry", "Biochemistry", "Developmental Biology", "Molecular Biology", "Cell Biology", "Genetics"], "users"=>["Hironori Waki", "Masahiro Nakamura", "Toshimasa Yamauchi", "Ken-ichi Wakabayashi", "Jing Yu", "Lisa Hirose-Yotsuya", "Kazumi Take", "Wei Sun", "Masato Iwabu", "Miki Okada-Iwabu", "Takanori Fujita", "Tomohisa Aoyama", "Shuichi Tsutsumi", "Kohjiro Ueki", "Tatsuhiko Kodama", "Juro Sakai", "Hiroyuki Aburatani", "Takashi Kadowaki"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002311.g008", "stats"=>{"downloads"=>2, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_NFI_occupy_the_adipocyte_specific_FAIRE_peaks_and_or_the_PPAR_947_binding_sites_near_PPAR_947_C_EBP_945_and_aP2_genes_/392082", "title"=>"NFI occupy the adipocyte-specific FAIRE peaks and/or the PPARγ binding sites near PPARγ, C/EBPα, and aP2 genes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-20 00:34:42"}

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  • {"unique-ip"=>"8", "full-text"=>"10", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
  • {"unique-ip"=>"12", "full-text"=>"14", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"13", "supp-data"=>"3", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"13", "full-text"=>"14", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"16", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
  • {"unique-ip"=>"9", "full-text"=>"8", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}
  • {"unique-ip"=>"19", "full-text"=>"15", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"19", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"8"}
  • {"unique-ip"=>"23", "full-text"=>"93", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2019", "month"=>"9"}

Relative Metric

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