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A highly orchestrated gene expression program establishes the properties that define mature adipocytes, but the contribution of posttranscriptional factors to the adipocyte phenotype is poorly understood. Here we have shown that the RNA-binding protein PSPC1, a component of the paraspeckle complex, promotes adipogenesis in vitro and is important for mature adipocyte function in vivo. Cross-linking and immunoprecipitation followed by RNA sequencing revealed that PSPC1 binds to intronic and 3'-untranslated regions of a number of adipocyte RNAs, including the RNA encoding the transcriptional regulator EBF1. Purification of the paraspeckle complex from adipocytes further showed that PSPC1 associates with the RNA export factor DDX3X in a differentiation-dependent manner. Remarkably, PSPC1 relocates from the nucleus to the cytoplasm during differentiation, coinciding with enhanced export of adipogenic RNAs. Mice lacking PSPC1 in fat displayed reduced lipid storage and adipose tissue mass and were resistant to diet-induced obesity and insulin resistance due to a compensatory increase in energy expenditure. These findings highlight a role for PSPC1-dependent RNA maturation in the posttranscriptional control of adipose development and function.

The KDM5 family of histone demethylases removes the H3K4 tri-methylation (H3K4me3) mark frequently found at promoter regions of actively transcribed genes and is therefore generally considered to contribute to corepression. In this study, we show that knockdown (KD) of all expressed members of the KDM5 family in white and brown preadipocytes leads to deregulated gene expression and blocks differentiation to mature adipocytes. KDM5 KD leads to a considerable increase in H3K4me3 at promoter regions; however, these changes in H3K4me3 have a limited effect on gene expression per se. By contrast, genome-wide analyses demonstrate that KDM5A is strongly enriched at KDM5-activated promoters, which generally have high levels of H3K4me3 and are associated with highly expressed genes. We show that KDM5-activated genes include a large set of cell cycle regulators and that the KDM5s are necessary for mitotic clonal expansion in 3T3-L1 cells, indicating that KDM5 KD may interfere with differentiation in part by impairing proliferation. Notably, the demethylase activity of KDM5A is required for activation of at least a subset of pro-proliferative cell cycle genes. In conclusion, the KDM5 family acts as dual modulators of gene expression in preadipocytes and is required for early stage differentiation and activation of pro-proliferative cell cycle genes., (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Adipocyte differentiation is controlled by a tightly regulated transcriptional cascade in which PPARgamma and members of the C/EBP family are key players. Here we review the roles of PPARgamma and C/EBPs in adipocyte differentiation with emphasis on the recently published genome-wide binding profiles for PPARgamma and C/EBPalpha. Interestingly, these analyses show that PPARgamma and C/EBPalpha binding sites are associated with most genes that are induced during adipogenesis suggesting direct activation of many more adipocyte genes than previously anticipated. Furthermore, an extensive overlap between the C/EBPalpha and PPARgamma cistromes indicate a hitherto unrecognized direct crosstalk between these transcription factors. As more genome-wide data emerge in the future, this crosstalk will likely be found to include several other adipogenic transcription factors., (Copyright (c) 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Summary: PPARγ and Wnt signaling are central positive and negative regulators of adipogenesis, respectively. Here we identify the groucho family member TLE3 as a transcriptional integrator of the PPARγ and Wnt pathways. TLE3 is a direct target of PPARγ that participates in a feed-forward loop during adipocyte differentiation. TLE3 enhances PPARγ activity and functions synergistically with PPARγ on its target promoters to stimulate adipogenesis. At the same time, induction of TLE3 during differentiation provides a mechanism for termination of Wnt signaling. TLE3 antagonizes TCF4 activation by β-catenin in preadipocytes, thereby inhibiting Wnt target gene expression and reversing β-catenin-dependent repression of adipocyte gene expression. Transgenic expression of TLE3 in adipose tissue in vivo mimics the effects of PPARγ agonist and ameliorates high-fat-diet-induced insulin resistance. Our data suggest that TLE3 acts as a dual-function switch, driving the formation of both active and repressive transcriptional complexes that facilitate the adipogenic program. [ABSTRACT FROM AUTHOR]

Abstract: Adipocyte differentiation is controlled by a tightly regulated transcriptional cascade in which PPARγ and members of the C/EBP family are key players. Here we review the roles of PPARγ and C/EBPs in adipocyte differentiation with emphasis on the recently published genome-wide binding profiles for PPARγ and C/EBPα. Interestingly, these analyses show that PPARγ and C/EBPα binding sites are associated with most genes that are induced during adipogenesis suggesting direct activation of many more adipocyte genes than previously anticipated. Furthermore, an extensive overlap between the C/EBPα and PPARγ cistromes indicate a hitherto unrecognized direct crosstalk between these transcription factors. As more genome-wide data emerge in the future, this crosstalk will likely be found to include several other adipogenic transcription factors. [ABSTRACT FROM AUTHOR]

Summary Interactions between transcriptional promoters and their distal regulatory elements play an important role in transcriptional regulation; however, the extent to which these interactions are subject to rapid modulations in response to signals is unknown. Here, we use promoter capture Hi-C to demonstrate a rapid reorganization of promoter-anchored chromatin loops within 4 hr after inducing differentiation of 3T3-L1 preadipocytes. The establishment of new promoter-enhancer loops is tightly coupled to activation of poised (histone H3 lysine 4 mono- and dimethylated) enhancers, as evidenced by the acquisition of histone H3 lysine 27 acetylation and the binding of MED1, SMC1, and P300 proteins to these regions, as well as to activation of target genes. Intriguingly, formation of loops connecting activated enhancers and promoters is also associated with extensive recruitment of corepressors such as NCoR and HDACs, indicating that this class of coregulators may play a previously unrecognized role during enhancer activation. [ABSTRACT FROM AUTHOR]