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Peroxisome Proliferator Activated Receptor Agonists Modulate Transposable Element Expression in Brain and Liver
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, respecti...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156381/ https://www.ncbi.nlm.nih.gov/pubmed/30283300 http://dx.doi.org/10.3389/fnmol.2018.00331 |
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author | Ferguson, Laura B. Zhang, Lingling Wang, Shi Bridges, Courtney Harris, R. Adron Ponomarev, Igor |
author_facet | Ferguson, Laura B. Zhang, Lingling Wang, Shi Bridges, Courtney Harris, R. Adron Ponomarev, Igor |
author_sort | Ferguson, Laura B. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6156381 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-61563812018-10-03 Peroxisome Proliferator Activated Receptor Agonists Modulate Transposable Element Expression in Brain and Liver Ferguson, Laura B. Zhang, Lingling Wang, Shi Bridges, Courtney Harris, R. Adron Ponomarev, Igor Front Mol Neurosci Molecular Neuroscience 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. Frontiers Media S.A. 2018-09-19 /pmc/articles/PMC6156381/ /pubmed/30283300 http://dx.doi.org/10.3389/fnmol.2018.00331 Text en Copyright © 2018 Ferguson, Zhang, Wang, Bridges, Harris and Ponomarev. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Molecular Neuroscience Ferguson, Laura B. Zhang, Lingling Wang, Shi Bridges, Courtney Harris, R. Adron Ponomarev, Igor Peroxisome Proliferator Activated Receptor Agonists Modulate Transposable Element Expression in Brain and Liver |
title | Peroxisome Proliferator Activated Receptor Agonists Modulate Transposable Element Expression in Brain and Liver |
title_full | Peroxisome Proliferator Activated Receptor Agonists Modulate Transposable Element Expression in Brain and Liver |
title_fullStr | Peroxisome Proliferator Activated Receptor Agonists Modulate Transposable Element Expression in Brain and Liver |
title_full_unstemmed | Peroxisome Proliferator Activated Receptor Agonists Modulate Transposable Element Expression in Brain and Liver |
title_short | Peroxisome Proliferator Activated Receptor Agonists Modulate Transposable Element Expression in Brain and Liver |
title_sort | peroxisome proliferator activated receptor agonists modulate transposable element expression in brain and liver |
topic | Molecular Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156381/ https://www.ncbi.nlm.nih.gov/pubmed/30283300 http://dx.doi.org/10.3389/fnmol.2018.00331 |
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