Global Mapping of Cell Type–Specific Open Chromatin by FAIRE-seq Reveals the Regulatory Role of the NFI Family in Adipocyte Differentiation

Waki, Hironori; Nakamura, Masahiro; Yamauchi, Toshimasa; Wakabayashi, K.; Yu, Jing; Hirose-Yotsuya, Lisa; Take, Kazumi; Sun, Wei; Iwabu, Masato; Okada-Iwabu, Miki; Fujita, Takanori; Aoyama, Tomohisa; Tsutsumi, Sadami; Ueki, Kohjiro; Kodama, Tatsuhiko; Sakai, Juro; Aburatani, Hiroyuki; Kadowaki, Takashi

doi:10.1371/journal.pgen.1002311

Cited by 108 publications

(122 citation statements)

References 84 publications

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“…The vast majority (85%) of the PPARγ-bound motif sites lie in regions of open chromatin, defined in terms of DNase hypersensitivity [as assayed by formaldehyde-assisted isolation of regulatory elements coupled with high-throughput sequencing (54)] and marked by H3K4me1/H3K27ac identified in adipocytes using ChIP-seq (47). Moreover, genomic PPARγ binding within open regions was strongly dependent on the quantitative DNA accessibility and the enrichment of chromatin marks such as H3K27ac ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Candidate enhancers containing additional PPARγ/RXR motif sites showed nearly twofold higher enhancer activity than those with only a single motif site. Third, the TFs that recognize several of the positively correlated motifs are known to promote adipocyte differentiation (64,65) or regulate gene expression in various stages of adipogenesis (54,(66)(67)(68)(69). Conversely, the TFs that recognize several of the negatively correlated motifs are transcriptional repressors involved in inhibiting adipocyte-specific genes (68,70) or promoting an alternate cell fate (71) (SI Appendix, Supplemental Note).…”

Section: Elements In the Sequence Flanking Pparγ Motifs Strongly Affectmentioning

confidence: 99%

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Systematic dissection of genomic features determining transcription factor binding and enhancer function

Grossman

Zhang

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

157

142

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Enhancers regulate gene expression through the binding of sequence-specific transcription factors (TFs) to cognate motifs. Various features influence TF binding and enhancer function-including the chromatin state of the genomic locus, the affinities of the binding site, the activity of the bound TFs, and interactions among TFs. However, the precise nature and relative contributions of these features remain unclear. Here, we used massively parallel reporter assays (MPRAs) involving 32,115 natural and synthetic enhancers, together with high-throughput in vivo binding assays, to systematically dissect the contribution of each of these features to the binding and activity of genomic regulatory elements that contain motifs for PPARγ, a TF that serves as a key regulator of adipogenesis. We show that distinct sets of features govern PPARγ binding vs. enhancer activity. PPARγ binding is largely governed by the affinity of the specific motif site and higher-order features of the larger genomic locus, such as chromatin accessibility. In contrast, the enhancer activity of PPARγ binding sites depends on varying contributions from dozens of TFs in the immediate vicinity, including interactions between combinations of these TFs. Different pairs of motifs follow different interaction rules, including subadditive, additive, and superadditive interactions among specific classes of TFs, with both spatially constrained and flexible grammars. Our results provide a paradigm for the systematic characterization of the genomic features underlying regulatory elements, applicable to the design of synthetic regulatory elements or the interpretation of human genetic variation.gene regulation | transcription factor binding | systems biology

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Section: Resultsmentioning

confidence: 99%

Section: Elements In the Sequence Flanking Pparγ Motifs Strongly Affectmentioning

confidence: 99%

Systematic dissection of genomic features determining transcription factor binding and enhancer function

Grossman

Zhang

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

157

142

View full text Add to dashboard Cite

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“…(88) Although their work was primarily focused on miR-382-5p in the context of cholesterol homeostasis and inflammation, while we studied miR-382-3p, as a byproduct Hu and colleagues experimentally validated nuclear factor IA (NFIA) as a target that is downregulated by miR-382-3p. Interestingly, NFIA was shown by Waki and colleagues (89) to be functionally required for proper adipocyte differentiation and lipid droplet formation.…”

Section: Discussionmentioning

confidence: 99%

Serum miRNA Signatures Are Indicative of Skeletal Fractures in Postmenopausal Women With and Without Type 2 Diabetes and Influence Osteogenic and Adipogenic Differentiation of Adipose Tissue–Derived Mesenchymal Stem Cells In Vitro

Heilmeier

Hackl²,

Skalicky

et al. 2016

Journal of Bone and Mineral Research

117

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Standard DXA measurements, including Fracture Risk Assessment Tool (FRAX) scores, have shown limitations in assessing fracture risk in Type 2 Diabetes (T2D), underscoring the need for novel biomarkers and suggesting that other pathomechanisms may drive diabetic bone fragility. MicroRNAs (miRNAs) are secreted into the circulation from cells of various tissues proportional to local disease severity and were recently found to be crucial to bone homeostasis and T2D. Here, we studied, if and which circulating miRNAs or combinations of miRNAs can discriminate best fracture status in a well-characterized study of diabetic bone disease and postmenopausal osteoporosis (n ¼ 80 postmenopausal women). We then tested the most discriminative and most frequent miRNAs in vitro. Using miRNA-qPCR-arrays, we showed that 48 miRNAs can differentiate fracture status in T2D women and that several combinations of four miRNAs can discriminate diabetes-related fractures with high specificity and sensitivity (area under the receiver-operating characteristic curve values [AUCs], 0.92 to 0.96; 95% CI, 0.88 to 0.98). For the osteoporotic study arm, 23 miRNAs were fracture-indicative and potential combinations of four miRNAs showed AUCs from 0.97 to 1.00 (95% CI, 0.93 to 1.00). Because a role in bone homeostasis for those miRNAs that were most discriminative and most present among all miRNA combinations had not been described, we performed in vitro functional studies in human adipose tissue-derived mesenchymal stem cells to investigate the effect of miR-550a-5p, miR-188-3p, and miR-382-3p on osteogenesis, adipogenesis, and cell proliferation. We found that miR-382-3p significantly enhanced osteogenic differentiation (p < 0.001), whereas miR-550a-5p inhibited this process (p < 0.001). Both miRNAs, miR-382-3p and miR-550a-5p, impaired adipogenic differentiation, whereas miR-188-3p did not exert an effect on adipogenesis. None of the miRNAs affected significantly cell proliferation. Our data suggest for the first time that miRNAs are linked to fragility fractures in T2D postmenopausal women and should be further investigated for their diagnostic potential and their detailed function in diabetic bone.

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“…Genomic DNA occurs in different configurations in distinct cell types [37]. Moreover, genome sizes range over more than five orders of magnitude (∼0.3-100,000 MB) [38].…”

Section: Formatting For Replication For Transmission To Daughter Cellsmentioning

confidence: 99%

How life changes itself: The Read–Write (RW) genome

Shapiro

2013

Physics of Life Reviews

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The genome has traditionally been treated as a Read-Only Memory (ROM) subject to change by copying errors and accidents. In this review, I propose that we need to change that perspective and understand the genome as an intricately formatted Read-Write (RW) data storage system constantly subject to cellular modifications and inscriptions. Cells operate under changing conditions and are continually modifying themselves by genome inscriptions. These inscriptions occur over three distinct time-scales (cell reproduction, multicellular development and evolutionary change) and involve a variety of different processes at each time scale (forming nucleoprotein complexes, epigenetic formatting and changes in DNA sequence structure). Research dating back to the 1930s has shown that genetic change is the result of cell-mediated processes, not simply accidents or damage to the DNA. This cell-active view of genome change applies to all scales of DNA sequence variation, from point mutations to large-scale genome rearrangements and whole genome duplications (WGDs). This conceptual change to active cell inscriptions controlling RW genome functions has profound implications for all areas of the life sciences.

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Global Mapping of Cell Type–Specific Open Chromatin by FAIRE-seq Reveals the Regulatory Role of the NFI Family in Adipocyte Differentiation

Cited by 108 publications

References 84 publications

Systematic dissection of genomic features determining transcription factor binding and enhancer function

Systematic dissection of genomic features determining transcription factor binding and enhancer function

Serum miRNA Signatures Are Indicative of Skeletal Fractures in Postmenopausal Women With and Without Type 2 Diabetes and Influence Osteogenic and Adipogenic Differentiation of Adipose Tissue–Derived Mesenchymal Stem Cells In Vitro

How life changes itself: The Read–Write (RW) genome

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