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Regulation of cyclic AMP response element binding and hippocampal plasticity-related genes by peroxisome proliferator-activated receptor ?.

ABSTRACT: Peroxisome proliferator-activated receptor ? (PPAR?) is a transcription factor that regulates genes involved in fatty acid catabolism. Here, we provide evidence that PPAR? is constitutively expressed in nuclei of hippocampal neurons and, surprisingly, controls calcium influx and the expression of various plasticity-related genes via direct transcriptional regulation of cyclic AMP response element binding (CREB). Accordingly, Ppar?-null, but not Ppar?-null, mice are deficient in CREB and memory-associated proteins and have decreased spatial learning and memory. Small hairpin RNA knockdown of PPAR? in the hippocampus suppressed CREB and NR2A, rendering wild-type animals markedly poor in consolidating spatial memory, whereas introduction of PPAR? to the hippocampus of Ppar?-null mice increased hippocampal CREB and NR2A and improved spatial learning and memory. Through detailed analyses of CREB and NR2A activity, as well as spatial learning and memory in bone marrow chimeric animals lacking PPAR? in the CNS, we uncover a mechanism for transcriptional control of Creb and associated plasticity genes by PPAR?.

SUBMITTER: Roy A

PROVIDER: S-EPMC3804033 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Regulation of cyclic AMP response element binding and hippocampal plasticity-related genes by peroxisome proliferator-activated receptor α.

Roy Avik A Jana Malabendu M Corbett Grant T GT Ramaswamy Shilpa S Kordower Jeffrey H JH Gonzalez Frank J FJ Pahan Kalipada K

Cell reports 20130822 4

Peroxisome proliferator-activated receptor α (PPARα) is a transcription factor that regulates genes involved in fatty acid catabolism. Here, we provide evidence that PPARα is constitutively expressed in nuclei of hippocampal neurons and, surprisingly, controls calcium influx and the expression of various plasticity-related genes via direct transcriptional regulation of cyclic AMP response element binding (CREB). Accordingly, Pparα-null, but not Pparβ-null, mice are deficient in CREB and memory-a ...[more]

PMID: 23972989

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Project 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.

Dataset Information

Regulation of cyclic AMP response element binding and hippocampal plasticity-related genes by peroxisome proliferator-activated receptor ?.

Publications

Regulation of cyclic AMP response element binding and hippocampal plasticity-related genes by peroxisome proliferator-activated receptor α.

Similar Datasets

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