Comparative transcriptomic and epigenomic analyses reveal new regulators of murine brown adipogenesis
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PROVIDER: PRJNA305097 | ENA |
REPOSITORIES: ENA
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Project description:Increasing energy expenditure by promoting the thermogenic program in brown adipocytes is a promising approach to combat human obesity. To fully exploit the potential of this approach a comprehensive understanding of the gene regulatory network that controls both lineage commitment and differentiation of brown cells is necessary. Here, we systematically examine the transcriptomic and epigenomic transitions from mesenchymal stem cells to brown adipocytes (BA) and we perform a comparative analysis with differentiating white adipocytes (WA). We identify coding genes, lncRNA genes, and microRNA genes that are differentially regulated upon BA differentiation. In addition, we generate genome wide reference maps for several chromatin marks throughout brown adipogenesis. We identify putative (super-)enhancers, super-enhancers controlled genes in brown and white adipocytes, as well as target genes of the brown lineage-committing factor BMP7. Finally we show that overexpression and knockdown of four putative novel adipogenic regulators (the kinase Pim1, and the transcription factors Six1, Rreb1, and Sox13), indeed affects BA differentiation, suggesting an important role in brown adipogenesis.
2016-12-31 | GSE75639 | GEO
Project description: Not available
| S-EPMC5140063 | biostudies-literature
Project description:Histone H3K4me1/2 methyltransferases MLL3/MLL4 and H3K27 acetyltransferases CBP/p300 are major enhancer epigenomic writers. To understand how these epigenomic writers orchestrate enhancer landscapes during cell differentiation, we have profiled genomic binding of MLL4, CBP, lineage-determining transcription factors, as well as transcriptome and epigenome during adipogenesis of immortalized preadipocytes derived from mouse brown adipose tissue (BAT). We show that MLL4 and CBP drive the dynamic enhancer epigenome, which correlates with the dynamic transcriptome. MLL3/MLL4 are required for CBP/p300 binding on enhancers activated during adipogenesis. Further, we show that MLL4 and CBP identify super-enhancers of adipogenesis and that MLL3/MLL4 are required for the formation of super-enhancers. Finally, in brown adipocytes differentiated in culture, MLL4 identifies primed super-enhancers of genes fully activated in BAT such as the thermogenic Ucp1. Comparison of MLL4-defined super-enhancers in brown and white adipogenesis predicted a list of brown-specific super-enhancers SEs associated genes that are likely to be important to BAT functions. These results establish MLL3/MLL4 and CBP/p300 as master enhancer epigenomic writers and suggest that enhancer-priming by MLL3/MLL4 followed by enhancer-activation by CBP/p300 sequentially shape dynamic enhancer landscapes during cell differentiation. Our data also provide a rich resource for understanding epigenomic regulation of brown adipogenesis.
2017-01-01 | GSE74189 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-12-31 | GSE75698 | GEO
Project description:Circular RNA Expression Profiles during brown adipogenesis
| PRJNA755181 | ENA
Project description:Obesity has emerged as a formidable health crisis due to its association with metabolic risk factors such as diabetes, dyslipidaemia and hypertension. Recent work has demonstrated the multifaceted roles of lncRNAs in regulating mouse adipose development, but its implication in human adipocytes remain largely unknown at least partially due to the lack of a comprehensive lncRNA catalog, particularly those specifically expressed in brown adipose tissue (BAT). In this study, we performed deep RNA-seq on adult subcutaneous, omental and fetal brown adipose tissues to de novo construct a catalog of 3,149 adipose active lncRNAs of which 1,351 are specifically detected in BAT. We further identified 318 lncRNAs conserved between human and mouse which, compared with non-conserved ones, are more broadly expressed in multiple cell types. One of these, lnc-dPRDM16, is transcribed divergently from Prdm16, tightly correlated with Prdm16 (R ≥ 0.7) in both mouse and human, and co-expressed (R ≥ 0.7) with protein-coding genes enriched in lipid and fatty acid catabolic processes. Loss of function of lnc-dPRDM16 led to a down-regulation of Prdm16 and an obvious reduction of adipogenesis in brown adipocyte culture. Together, our work has provided a comprehensive human adipose catalog built from diverse fat types, which when applied to our roadmap, identifies lnc-dPRDM16 as a promising modulator of adipose development for future clinical research.
2018-04-16 | GSE97205 | GEO
Project description:PPARγ promotes adipogenesis while Wnt proteins inhibit adipogenesis. However, the mechanisms that control expression of these positive and negative master regulators of adipogenesis remain incompletely understood. By genome-wide histone methylation profiling in preadipocytes, we find that among gene loci encoding adipogenesis regulators, histone methyltransferase (HMT) G9a-mediated repressive epigenetic mark H3K9me2 is enriched on the entire PPARγ locus. H3K9me2 and G9a levels decrease during adipogenesis, which correlates inversely with induction of PPARγ. Removal of H3K9me2 by G9a deletion enhances chromatin opening and binding of adipogenic transcription factor C/EBP-beta to PPARγ promoter, which promotes PPARγ expression. Interestingly, G9a represses PPARγ expression in an HMT activity-dependent manner but facilitates Wnt10a expression independent of its enzymatic activity. Consistently, deletion of G9a or inhibiting G9a HMT activity promotes adipogenesis. Finally, deletion of G9a in mouse adipose tissues increases adipogenic gene expression and tissue weight. Thus, by inhibiting PPARγ expression and facilitating Wnt10a expression, G9a represses adipogenesis. Examination of gene expression changes in G9a KO brown preadipocytes
2013-02-01 | E-GEOD-41456 | biostudies-arrayexpress
Project description:Secreted proteins from adipose tissue play a role in metabolic cross-talk and homeostasis. We performed high sensitivity mass spectrometry-based proteomics on the cell media of human adipocytes derived from the supraclavicular brown adipose and from the subcutaneous white adipose depots of adult humans. We identified 471 potentially secreted proteins covering interesting protein categories such as hormones, growth factors, extracellular matrix proteins and proteins of the complement system, which were differentially regulated in brown and white adipocytes. A total of 101 proteins were exclusively quantified in brown adipocytes and among these were ependymin-related protein 1 (EPDR1). Functional studies suggested a role for EPDR1 in thermogenic adipogenesis. In conclusion, we report substantial differences between the secretomes of brown and white human adipocytes and identify novel candidate batokines that can be important regulators of metabolism.
2019-10-03 | PXD008541 | Pride
Project description:Insulin action initiates a series of phosphorylation events regulating cellular differentiation, growth and metabolism. We have previously discovered, in a mass spectrometry-based phosphoproteomic study, that insulin/IGF-1 signaling induces phosphorylation of retinoid x receptor alpha (RXRα) at S22 in mouse brown pre-adipocytes. Here, we show that insulin induces the phosphorylation of RXRα at S22 in both brown precursor and mature adipocytes through a pathway involving ERK, downstream of IRS-1 and -2. We also found that RXRα S22 phosphorylation is promoted by insulin and upon re-feeding in brown adipose tissue in vivo, and that insulin-stimulated S22 phosphorylation of RXRα is dampened by diet-induced obesity. We used Rxra knockout cells re-expressing wild type (WT) or S22A non-phosphorylatable forms of RXRα to further characterize the role of S22 in brown adipocytes. Knockout of Rxra in brown pre-adipocytes resulted in decreased lipid accumulation and adipogenic gene expression during differentiation, and re-expression of RxraWT alleviated these effects. However, we observed no significant difference in cells re-expressing the RxraS22A mutant as compared with the cells re-expressing RxraWT. Furthermore, comparison of gene expression during adipogenesis in the WT and S22A re-expressing cells by RNA sequencing revealed similar transcriptomic profiles. Thus, our data propose a dispensable role for RXRα S22 phosphorylation in adipogenesis and transcription in differentiating brown pre-adipocytes.
2020-03-30 | GSE147687 | GEO
Project description:Dexamethasone (DEX), a synthetic ligand for glucocorticoid receptor (GR), is routinely used to stimulate adipogenesis in culture. GR-depleted preadipocytes show adipogenesis defects one week after induction of differentiation. However, it has remained unclear whether GR is required for adipogenesis in vivo. By deleting GR in precursors of brown adipocytes, we found unexpectedly that GR is dispensable for brown adipose tissue development in mice. In culture, GR-deficient primary or immortalized white and brown preadipocytes showed severely delayed adipogenesis one week after induction of differentiation. However, when differentiation was extended to 3 weeks, GR-deficient preadipocytes showed similar levels of adipogenesis marker expression and lipid accumulation as the wild type cells, indicating that DEX-bound GR accelerates, but is dispensable for, adipogenesis. Consistently, DEX accelerates, but is dispensable for, adipogenesis in culture. We show that DEX-bound GR accelerates adipogenesis by directly promoting the expression of adipogenic transcription factors C/EBPb, C/EBPd, C/EBPa, KLF5, KLF9 and PPARg in the early phase of differentiation. Mechanistically, DEX-bound GR recruits histone H3K27 acetyltransferase CBP to promote activation of C/EBPb-primed enhancers of adipogenic genes. These results clarify the role of GR in adipogenesis in vivo and demonstrate that DEX-mediated activation of GR accelerates, but is dispensable for, adipogenesis.
2016-11-01 | GSE76619 | GEO