Adipocytes Fail to Maintain Cellular Identity During Obesity Due to Reduced PPARg Activity and Elevated TGFβ-SMAD Signaling
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ABSTRACT:
PROVIDER: PRJNA641491 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12078557_1.fastq.gz | Fastqsanger.gz | |||
| SRR12078557_2.fastq.gz | Fastqsanger.gz | |||
| SRR12078558_1.fastq.gz | Fastqsanger.gz | |||
| SRR12078558_2.fastq.gz | Fastqsanger.gz | |||
| SRR12078559_1.fastq.gz | Fastqsanger.gz |
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Project description:Obesity due to overnutrition causes adipose tissue dysfunction, serving as a critical pathological step on the road to Type 2 diabetes (T2D) and other metabolic disorders. Here, we performed an unbiased investigation into the fundamental molecular mechanisms by which adipocytes transition to an unhealthy state during obesity. We fed NuTRAP (Nuclear tagging and Translating Ribosome Affinity Purification) mice crossed with Adipoq-Cre with chow or high fat diet (HFD) for 10 weeks and determined adipocyte-specific transcriptomic profiles by RNA-seq, active promoter and enhancer activities by H3K27ac ChIP-seq, and the PPARg cistrome by ChIP-seq. We also assessed the impact of the PPARg agonist rosiglitazone (Rosi) on gene expression and cellular state of adipocytes from HFD-fed mice. We used bioinformatic approaches to find transcriptional pathways and performed functional studies using shRNA-mediated loss-of-function approaches in 3T3-L1 adipocytes. Adipocytes from HFD-fed mice exhibited reduced expression of adipocyte markers and metabolic genes while showing enhanced expression of myofibroblast marker genes involved in cytoskeletal organization, accompanied by the formation of actin filament structures within the cell. PPARg binding was globally reduced in adipocytes after HFD feeding, and Rosi restored the molecular and cellular phenotypes of adipocytes associated with HFD feeding. SMAD binding motifs were over-represented in HFD-induced promoters and enhancers, while TGFb1 expression was elevated in adipose tissues after HFD feeding. TGFb1 treatment of mature 3T3-L1 adipocytes induced gene expression and cellular changes similar to those seen after HFD in vivo, and knockdown of Smad3 blunted the effects of TGFb1. Our data demonstrate that adipocytes fail to maintain cellular identity after HFD, acquiring characteristics of a myofibroblast-like cell type through reduced PPARg activity and elevated TGFb-SMAD signaling. This cellular identity crisis may serve as a fundamental mechanism that drives functional decline of adipose tissues during obesity.
2020-07-05 | GSE153120 | GEO
Project description:OBJECTIVE:Obesity due to overnutrition causes adipose tissue dysfunction, which is a critical pathological step on the road to type 2 diabetes (T2D) and other metabolic disorders. In this study, we conducted an unbiased investigation into the fundamental molecular mechanisms by which adipocytes transition to an unhealthy state during obesity. METHODS:We used nuclear tagging and translating ribosome affinity purification (NuTRAP) reporter mice crossed with Adipoq-Cre mice to determine adipocyte-specific 1) transcriptional profiles (RNA-seq), 2) promoter and enhancer activity (H3K27ac ChIP-seq), 3) and PPAR? cistrome (ChIP-seq) profiles in mice fed chow or a high-fat diet (HFD) for 10 weeks. We also assessed the impact of the PPAR? agonist rosiglitazone (Rosi) on gene expression and cellular state of adipocytes from the HFD-fed mice. We integrated these data to determine the transcription factors underlying adipocyte responses to HFD and conducted functional studies using shRNA-mediated loss-of-function approaches in 3T3-L1 adipocytes. RESULTS:Adipocytes from the HFD-fed mice exhibited reduced expression of adipocyte markers and metabolic genes and enhanced expression of myofibroblast marker genes involved in cytoskeletal organization, accompanied by the formation of actin filament structures within the cell. PPAR? binding was globally reduced in adipocytes after HFD feeding, and Rosi restored the molecular and cellular phenotypes of adipocytes associated with HFD feeding. We identified the TGF?1 effector protein SMAD to be enriched at HFD-induced promoters and enhancers and associated with myofibroblast signature genes. TGF?1 treatment of mature 3T3-L1 adipocytes induced gene expression and cellular changes similar to those seen after HFD in vivo, and knockdown of Smad3 blunted the effects of TGF?1. CONCLUSIONS:Our data demonstrate that adipocytes fail to maintain cellular identity after HFD feeding, acquiring characteristics of a myofibroblast-like cell type through reduced PPAR? activity and elevated TGF?-SMAD signaling. This cellular identity crisis may be a fundamental mechanism that drives functional decline of adipose tissues during obesity.
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Project description:SMAD-mediated signaling regulates a broad range of cell fate decisions including apoptosis, cell cycle arrest and EMT. To elucidate how this relatively simple pathway realizes this complexity, we systematically investigate how SMAD-mediated responses are modulated by various ligands of the TGFβ family, and compare these ligand responses in quiescent and proliferating MCF10A cells.
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2024-02-05 | E-MTAB-12879 | biostudies-arrayexpress
Project description:Cholangiocarcinoma (CCA) is a devastating liver cancer characterized by high aggressiveness and resistance to therapy, which results to poor prognosis. Signals imposed by oncogenic pathways, such as transforming growth factor β (TGFβ) frequently contribute to CCA development. In this study, we explored novel effectors of the TGFβ pathway in CCA by gene expression profiling. We identified the long non-coding RNA LINC00313 as a novel target gene of TGFβ signalling in CCA cells. TGFβ induced LINC00313 expression in a TβRI/Smad-dependent manner. Subcellular fractionation showed that LINC00313 is a predominantly nuclear lncRNA. By integrating RNA-seq and ATAC-seq data from LINC00313 over-expressing cells, we observed that LINC00313 regulates the expression of several genes involved in the Wnt signalling pathway. As a proof of concept, we focused on the gene encoding transcription factor 7 (TCF7), a major effector that drives transcription of Wnt-target genes. LINC00313 gain of function resulted in increased TCF7 expression, while its loss of function diminished basal or TGFβ-induced TCF7 expression levels. Interestingly, LINC00313 enhanced basal or chemically induced TCF/LEF-dependent transcriptional responses, promoted colony-forming capacities of CCA cells in vitro and accelerated tumor growth in vivo. We also report that genes associated with LINC00313 over-expression recapitulate poor prognosis human CCA associated with a reduced overall survival and KRAS mutations. To decipher the underlying molecular functions of LINC00313, we identified its interacting proteins by performing an unbiased RNA pull-down assay followed by mass spectrometry. We demonstrated that actin-like 6A (ACTL6A), a subunit of the SWI/SNF chromatin remodelling complex specifically binds to LINC00313 and impacts TCF7 expression and TCF/LEF signalling output. Thus, we propose a model whereby TGFβ induces LINC00313, in order to regulate the expression of a subset of target genes, such as TCF7 possibly in co-operation with the SWI/SNF chromatin remodelling complex, via establishing direct interaction with ACTL6A. By regulating key genes of the Wnt pathway, LINC00313 fine-tunes Wnt/TCF/LEF-dependent transcriptional responses and boosts cholangiocarcinogenesis.
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