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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2018.00596

Temporal integrative analysis of mRNA and microRNAs expression profiles and epigenetic alterations in female SAMP8, a model of age-related cognitive decline

  • 1University of Barcelona, Spain
  • 2Instituto Tecnológico y de Estudios Superiores de Monterrey, Mexico
  • 3Universidad de Guadalajara, Mexico

A growing body of research shows that epigenetic mechanisms are critically involved in normal and pathological aging. The Senescence-Accelerated Mouse Prone 8 (SAMP8) can be considered a useful tool to better understand the dynamics of the global epigenetic landscape during the aging process since its phenotype is not fully explained by genetic factors.
Here we investigated dysfunctional age-related transcriptional profiles and epigenetic programming enzymes in the hippocampus of 2- and 9-month-old SAMP8 female mice using the Senescent-Accelerated Resistant 1 (SAMR1) mouse strain as control.
SAMP8 mice presented 1,062 genes dysregulated at 2 months of age, and 1,033 genes at 9 months, with 92 genes concurrently dysregulated at both ages compared to age-matched SAMR1. SAMP8 mice showed a significant decrease in global DNA methylation (5-mC) at 2 months while hydroxymethylation (5-hmC) levels were increased in SAMP8 mice at 2 and 9 months of age compared to SAMR1. These changes were accompanied by changes in the expression of several enzymes that regulate 5-mC and methylcytosine oxidation. Acetylated H3 and H4 histone levels were significantly diminished in SAMP8 mice at 2-month-old compared to SAMR1 and altered Histone DeACetylase (HDACs) profiles were detected in both young and old SAMP8 mice. We analyzed 84 different mouse miRNAs known to be altered in neurological diseases or involved in neuronal development. Compared with SAMR1, SAMP8 mice showed 28 and 17 miRNAs differentially expressed at 2 and 9 months of age, respectively; 6 of these miRNAs overlapped at both ages. We used several bioinformatic approaches to integrate our data in mRNA:miRNA regulatory networks and functional predictions for young and aged animals.
In sum, our study reveals interplay between epigenetic mechanisms and gene networks that seems to be relevant for the progression towards a pathological aging and provides several potential markers and therapeutic candidates for Alzheimer’s Disease (AD) and age-related cognitive impairment.

Keywords: Epigenetics (MeSH), Alzheimer ' s disease, chromatin-modifying enzymes, Brain, Aging, microRNA (miR), DNA methylation (DNAm)

Received: 02 Sep 2018; Accepted: 15 Nov 2018.

Edited by:

Ruth Luthi-Carter, University of Leicester, United Kingdom

Reviewed by:

Rupert W. Overall, Deutsche Zentrum für Neurodegenerative Erkrankungen, Helmholtz-Gemeinschaft Deutscher Forschungszentren (HZ), Germany
Elizabeth A. Thomas, The Scripps Research Institute, United States  

Copyright: © 2018 Cosín-Tomás, Álvarez-López, Companys-Alemany, Kaliman, González-Castillo, Ortuño-Sahagún, Pallàs and Griñán-Ferré. 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.

* Correspondence: Dr. Mercè Pallàs, University of Barcelona, Barcelona, Spain, pallas@ub.edu