Promoter–enhancer looping at the PPARγ2 locus during adipogenic differentiation requires the Prmt5 methyltransferase

LeBlanc, Scott E.; Wu, Qiong; Lamba, Pallavi; Sif, Saı̈d

doi:10.1093/nar/gkw129

Cited by 34 publications

(37 citation statements)

References 76 publications

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“…When PRMT5 is overexpressed, adipogenesis increases; on the other hand, the inhibition of PRMT5 resulted in the repression of adipogenic genes. Thus, PRMT5 plays a role in coactivation for adipogenic gene expression and adipogenesis [106,107].…”

Section: Histone Methylationmentioning

confidence: 99%

Adipogenesis: A Complex Interplay of Multiple Molecular Determinants and Pathways

Ambele

Dhanraj

Giles

2020

IJMS

183

146

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The formation of adipocytes during embryogenesis has been largely understudied. However, preadipocytes appear to originate from multipotent mesenchymal stromal/stem cells which migrate from the mesoderm to their anatomical localization. Most studies on adipocyte formation (adipogenesis) have used preadipocytes derived from adult stem/stromal cells. Adipogenesis consists of two phases, namely commitment and terminal differentiation. This review discusses the role of signalling pathways, epigenetic modifiers, and transcription factors in preadipocyte commitment and differentiation into mature adipocytes, as well as limitations in our understanding of these processes. To date, a limited number of transcription factors, genes and signalling pathways have been described to regulate preadipocyte commitment. One reason could be that most studies on adipogenesis have used preadipocytes already committed to the adipogenic lineage, which are therefore not suitable for studying preadipocyte commitment. Conversely, over a dozen molecular players including transcription factors, genes, signalling pathways, epigenetic regulators, and microRNAs have been described to be involved in the differentiation of preadipocytes to adipocytes; however, only peroxisome proliferator-activated receptor gamma has proven to be clinically relevant. A detailed understanding of how the molecular players underpinning adipogenesis relate to adipose tissue function could provide new therapeutic approaches for addressing obesity without compromising adipose tissue function.

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Section: Histone Methylationmentioning

confidence: 99%

Adipogenesis: A Complex Interplay of Multiple Molecular Determinants and Pathways

Ambele

Dhanraj

Giles

2020

IJMS

183

146

View full text Add to dashboard Cite

show abstract

“…Knockdown of Prmt5 inhibits adipogenesis and adipogenic gene expression in 3T3-L1 and C3H10T1/2 cells. A recent study used chromosome conformation capture assay and identified a differentiation-dependent and Prmt5-dependent interaction between Pparg2 promoter and kb Ϫ10 enhancer regions in C3H10T1/2 cells after differentiation (119). Prmt5 is also required for Med1 and Brg1 binding at the Pparg2 promoter and the kb Ϫ10 enhancer.…”

Section: Epigenomic Regulation Of Adipogenesismentioning

confidence: 99%

Transcriptional and Epigenomic Regulation of Adipogenesis

Lee

Schmidt

Lai

et al. 2019

Molecular and Cellular Biology

206

178

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Understanding adipogenesis, the process of adipocyte development, may provide new ways to treat obesity and related metabolic diseases. Adipogenesis is controlled by coordinated actions of lineage-determining transcription factors and epigenomic regulators. Peroxisome proliferator-activated receptor gamma (PPAR␥) and C/EBP␣ are master "adipogenic" transcription factors. In recent years, a growing number of studies have reported the identification of novel transcriptional and epigenomic regulators of adipogenesis. However, many of these novel regulators have not been validated in adipocyte development in vivo and their working mechanisms are often far from clear. In this minireview, we discuss recent advances in transcriptional and epigenomic regulation of adipogenesis, with a focus on factors and mechanisms shared by both white adipogenesis and brown adipogenesis. Studies on the transcriptional regulation of adipogenesis highlight the importance of investigating adipocyte differentiation in vivo rather than drawing conclusions based on knockdown experiments in cell culture. Advances in understanding of epigenomic regulation of adipogenesis have revealed critical roles of histone methylation/demethylation, histone acetylation/deacetylation, chromatin remodeling, DNA methylation, and microRNAs in adipocyte differentiation. We also discuss future research directions that may help identify novel factors and mechanisms regulating adipogenesis.

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“…It is important to translate the SNPs associations into causal genes and biological pathways underlying the pathogenesis of osteoporosis. Recent studies have found that noncoding SNPs could regulate expressions of distal genes by long-range interactions, (17)(18)(19)(20)(21)(22)(23)(24) which provide us new insights into deciphering the relationship between noncoding SNPs and diseases.…”

Section: Introductionmentioning

confidence: 99%

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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Promoter–enhancer looping at the PPARγ2 locus during adipogenic differentiation requires the Prmt5 methyltransferase

Cited by 34 publications

References 76 publications

Adipogenesis: A Complex Interplay of Multiple Molecular Determinants and Pathways

Adipogenesis: A Complex Interplay of Multiple Molecular Determinants and Pathways

Transcriptional and Epigenomic Regulation of Adipogenesis

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

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