Nuclear factor I‐C reciprocally regulates adipocyte and osteoblast differentiation
            <i>via</i>
            control of canonical Wnt signaling

Zhou, Jie; Wang, Shan; Qi, Qi; Yang, Xiaoyue; Zhu, Endong; Yuan, Hairui; Li, Xuemei; Liu, Ying; Li, Xiaoxia; Wang, Baoli

doi:10.1096/fj.201600975rr

Cited by 36 publications

(36 citation statements)

References 51 publications

(55 reference statements)

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“…Particularly, NFIC mRNA has the highest expression in normal osteoblast among them . Our data implicated NFIC as a mediator of risk for osteoporosis, which is consistent with previous reports of the functions of NFIC . Interestingly, the expression of Rankl was decreased in Nfic –/– mice.…”

Section: Discussionsupporting

confidence: 66%

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Multiple Functional Variants at 13q14 Risk Locus for Osteoporosis Regulate RANKL Expression Through Long-Range Super-Enhancer

Zhu

Chen

et al. 2018

Journal of Bone and Mineral Research

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RANKL is a key regulator involved in bone metabolism, and a drug target for osteoporosis. The clinical diagnosis and assessment of osteoporosis are mainly based on bone mineral density (BMD). Previous powerful genomewide association studies (GWASs) have identified multiple intergenic single-nucleotide polymorphisms (SNPs) located over 100 kb upstream of RANKL and 65 kb downstream of AKAP11 at 13q14.11 for osteoporosis. Whether these SNPs exert their roles on osteoporosis through RANKL is unknown. In this study, we conducted integrative analyses combining expression quantitative trait locus (eQTL), genomic chromatin interaction (high-throughput chromosome conformation capture [Hi-C]), epigenetic annotation, and a series of functional assays. The eQTL analysis identified six potential functional SNPs (rs9533090, rs9594738, r8001611, rs9533094, rs9533095, and rs9594759) exclusively correlated with RANKL gene expression (p < 0.001) at 13q14.11. Co-localization analyses suggested that eQTL signal for RANKL and BMD-GWAS signal shared the same causal variants. Hi-C analysis and functional annotation further validated that the first five osteoporosis SNPs are located in a super-enhancer region to regulate the expression of RANKL via long-range chromosomal interaction. Particularly, dual-luciferase assay showed that the region harboring rs9533090 in the super-enhancer has the strongest enhancer activity, and rs9533090 is an allele-specific regulatory SNP. Furthermore, deletion of the region harboring rs9533090 using CRISPR/Cas9 genome editing significantly reduced RANKL expression in both mRNA level and protein level. Finally, we found that the rs9533090-C robustly recruits transcription factor NFIC, which efficiently elevates the enhancer activity and increases the RANKL expression. In summary, we provided a feasible method to identify regulatory noncoding SNPs to distally regulate their target gene underlying the pathogenesis of osteoporosis by using bioinformatics data analyses and experimental validation. Our findings would be a potential and promising therapeutic target for precision medicine in osteoporosis. © 2018 American Society for Bone and Mineral Research.

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Section: Discussionsupporting

confidence: 66%

“…(65) Our data implicated NFIC as a mediator of risk for osteoporosis, which is consistent with previous reports of the functions of NFIC. (65,66) Interestingly, the expression of Rankl was decreased in Nfic -/mice. Disruption of NFIC impairs osteoblast differentiation and bone formation in vivo.…”

Section: Journal Of Bone and Mineral Researchmentioning

confidence: 98%

Multiple Functional Variants at 13q14 Risk Locus for Osteoporosis Regulate RANKL Expression Through Long-Range Super-Enhancer

Zhu

Chen

et al. 2018

Journal of Bone and Mineral Research

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“…Supportively, a transcriptome analysis independently suggested that NFIA would be a positive regulator of brown adipocyte differentiation 40 . Interestingly, it is reported that NFIC negatively regulates adipocyte differentiation 41 . Future studies will be needed to understand the mechanisms underlying differential regulation of brown adipocyte differentiation by different isoforms of NFI family.…”

Section: Discussionmentioning

confidence: 99%

NFIA co-localizes with PPARγ and transcriptionally controls the brown fat gene program

Hiraike

Waki

et al. 2017

Nat Cell Biol

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Brown fat dissipates energy as heat and protects against obesity. Here, we identified nuclear factor I-A (NFIA) as a transcriptional regulator of brown fat by a genome-wide open chromatin analysis of murine brown and white fat followed by motif analysis of brown-fat-specific open chromatin regions. NFIA and the master transcriptional regulator of adipogenesis, PPARγ, co-localize at the brown-fat-specific enhancers. Moreover, the binding of NFIA precedes and facilitates the binding of PPARγ, leading to increased chromatin accessibility and active transcription. Introduction of NFIA into myoblasts results in brown adipocyte differentiation. Conversely, the brown fat of NFIA knockout mice displays impaired expression of the brown-fat-specific genes and reciprocal elevation of muscle genes. Finally, expression of NFIA and the brown-fat-specific genes is positively correlated in human brown fat. These results indicate that NFIA activates the cell-type-specific enhancers and facilitates the binding of PPARγ for controlling the brown fat gene program.

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“…BMSCs were isolated from femurs and tibias of 4-week-old C57BL/6J mice and cultured in α-MEM supplemented with 10% fetal bovine serum (FBS) in 10 cm dish as previously described (Zhou et al 2017). When cells reached about 90% confluences, they were cultured in adipocyte-inducing medium (AIM, α-MEM containing 10% FBS, 0.5 mM dexamethasone, 0.25 mM methylisobutylxanthine, 5 mg/mL of insulin, and 50 mM indomethacin) for 72 h, followed by treatment for an additional 48 h with 5 mg/mL insulin alone.…”

Section: Cells Culturementioning

confidence: 99%

miR-20a-5p promotes adipogenic differentiation of murine bone marrow stromal cells via targeting Kruppel-like factor 3

Zhu¹,

Zhang²,

Zhou³

et al. 2018

Journal of Molecular Endocrinology

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miR-20a-5p has recently been identified to induce adipogenesis of established adipogenic cell lines in our previous study. However, its role and molecular mechanisms in the regulation of adipocyte lineage commitment of bone marrow-derived stromal cells (BMSCs) still need to be explored. In this report, we demonstrated the expression of miR-20a-5p was promoted gradually during adipogenic differentiation in BMSCs. We also confirmed that miR-20a-5p has a positive function in the adipogenic differentiation of BMSCs by gain-of-function study with overexpression lentivirus or synthetic mimics of miR-20a-5p, and loss-of-function study with sponge lentivirus or synthetic inhibitor of miR-20a-5p. Dual luciferase reporter assay, GFP repression assay and Western blotting suggested Kruppel-like factor 3 () was a direct target of miR-20a-5p. Furthermore, siRNA-mediated silencing of recapitulated the potentiation of adipogenesis induced by miR-20a-5p overexpression, whereas enhanced expression of attenuated the effect of miR-20a-5p. As was reported to play an inhibitory role in adipogenesis at the initial stage of differentiation, the findings we present here indicate that miR-20a-5p promotes adipocyte differentiation from BMSCs by targeting and negatively regulating in the early phase during the procedure of adipogenesis.

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Nuclear factor I‐C reciprocally regulates adipocyte and osteoblast differentiation via control of canonical Wnt signaling

Cited by 36 publications

References 51 publications

Multiple Functional Variants at 13q14 Risk Locus for Osteoporosis Regulate RANKL Expression Through Long-Range Super-Enhancer

Multiple Functional Variants at 13q14 Risk Locus for Osteoporosis Regulate RANKL Expression Through Long-Range Super-Enhancer

NFIA co-localizes with PPARγ and transcriptionally controls the brown fat gene program

miR-20a-5p promotes adipogenic differentiation of murine bone marrow stromal cells via targeting Kruppel-like factor 3

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