Abstract
Peroxisome proliferator activated receptors (PPARs) are nuclear hormone receptors that act as transcription factors in response to endogenous lipid messengers. The fibrates and thiazolidinediones are synthetic PPAR agonists used clinically to treat dyslipidemia and Type 2 Diabetes Mellitus, respectively, but also improve symptoms of several other diseases. Transposable elements (TEs), repetitive sequences in mammalian genomes, are implicated in many of the same conditions for which PPAR agonists are therapeutic, including neurodegeneration, schizophrenia, and drug addiction. We tested the hypothesis that there is a link between actions of PPAR agonists and TE expression. We developed an innovative application of microarray data by mapping Illumina mouse WG-6 microarray probes to areas of the mouse genome that contain TEs. Using this information, we assessed the effects of systemic administration of three PPAR agonists with different PPAR subtype selectivity: fenofibrate, tesaglitazar, and bezafibrate, on TE probe expression in mouse brain [prefrontal cortex (PFC) and amygdala] and liver. We found that fenofibrate, and bezafibrate to a lesser extent, up-regulated probes mapped to retrotransposons: Short-Interspersed Elements (SINEs) and Long-Interspersed Elements (LINEs), in the PFC. Conversely, all PPAR agonists down-regulated LINEs and tesaglitazar and bezafibrate also down-regulated SINEs in liver. We built gene coexpression networks that partitioned the diverse transcriptional response to PPAR agonists into groups of probes with highly correlated expression patterns (modules). Most of the differentially expressed retrotransposons were within the same module, suggesting coordinated regulation of their expression, possibly by PPAR signaling. One TE module was conserved across tissues and was enriched with genes whose products participate in epigenetic regulation, suggesting that PPAR agonists affect TE expression via epigenetic mechanisms. Other enriched functional categories included phenotypes related to embryonic development and learning and memory, suggesting functional links between these biological processes and TE expression. In summary, these findings suggest mechanistic relationships between retrotransposons and PPAR agonists and provide a basis for future exploration of their functional roles in brain and liver.
Highlights
Peroxisome proliferator activated receptors (PPARs), members of the nuclear hormone receptor family, are ligand-activated transcription factors
We previously studied the organization of brain transcriptome in human alcoholics and discovered that Transposable elements (TEs), such as long-term repeat (LTR) and Short-Interspersed Elements (SINEs), are co-expressed and regulated in alcoholics (Ponomarev et al, 2012)
We performed TE enrichment analysis to determine if a TE regulation exists in mouse, and if PPAR agonist treatment has any effect on TE regulation
Summary
Peroxisome proliferator activated receptors (PPARs), members of the nuclear hormone receptor family, are ligand-activated transcription factors. There are three PPAR isotypes: PPARα, PPARγ and PPARβ (sometimes called PPARδ) with distinct expression patterns, tissue distribution, and ligand specificity (Grygiel-Gorniak, 2014). All PPAR isotypes are expressed in brain, including the prefrontal cortex (PFC) and amygdala, and appear to be most highly expressed in neurons (Moreno et al, 2004; Warden et al, 2016). Their main function is to regulate fatty acid metabolism and have roles in inflammation, glucose metabolism, adipogenesis and myelination [for review, see (Tyagi et al, 2011)]. PPARβ /PPARδ agonists are not used clinically, they have been used as performance enhancers by athletes and have been prohibited by the World Anti-Doping Agency
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