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Sökning: WFRF:(Melas M) > (2010-2014)

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  • Melas, P. A., et al. (författare)
  • Allele-specific programming of Npy and epigenetic effects of physical activity in a genetic model of depression
  • 2013
  • Ingår i: Translational Psychiatry. - 2158-3188 .- 2158-3188. ; 3, s. e255-
  • Tidskriftsartikel (refereegranskat)abstract
    • Neuropeptide Y (NPY) has been implicated in depression, emotional processing and stress response. Part of this evidence originates from human single-nucleotide polymorphism (SNP) studies. In the present study, we report that a SNP in the rat Npy promoter (C/T; rs105431668) affects in vitro transcription and DNA-protein interactions. Genotyping studies showed that the C-allele of rs105431668 is present in a genetic rat model of depression (Flinders sensitive line; FSL), while the SNP's T-allele is present in its controls (Flinders resistant line; FRL). In vivo experiments revealed binding of a transcription factor (CREB2) and a histone acetyltransferase (Ep300) only at the SNP locus of the FRL. Accordingly, the FRL had increased hippocampal levels of Npy mRNA and H3K18 acetylation; a gene-activating histone modification maintained by Ep300. Next, based on previous studies showing antidepressant-like effects of physical activity in the FSL, we hypothesized that physical activity may affect Npy's epigenetic status. In line with this assumption, physical activity was associated with increased levels of Npy mRNA and H3K18 acetylation. Physical activity was also associated with reduced mRNA levels of a histone deacetylase (Hdac5). Conclusively, the rat rs105431668 appears to be a functional Npy SNP that may underlie depression-like characteristics. In addition, the achieved epigenetic reprogramming of Npy provides molecular support for the putative effectiveness of physical activity as a non-pharmacological antidepressant.
  • Melas, Philippe A., et al. (författare)
  • Neuropeptide Y : Identification of a novel rat mRNA splice-variant that is downregulated in the hippocampus and the prefrontal cortex of a depression-like model
  • 2012
  • Ingår i: Peptides. - 0196-9781 .- 1873-5169. ; 35:1, s. 49-55
  • Tidskriftsartikel (refereegranskat)abstract
    • Neuropeptide Y (NPY) is known to influence emotional processing and decreased NPY levels have been associated with mood and anxiety disorders. Alternative splicing of pre-messenger RNA is a cellular mechanism that allows for transcriptome diversity, yet there is limited knowledge in this respect with regard to Npy. Since the hippocampus and the prefrontal cortex play an important role in affective disorders, we investigated alternative splicing of Npy in these regions of a rat model of depression (Flinders Sensitive Line, FSL) and its controls (Flinders Resistant Line, FRL). The existence of different Npy messenger RNA (mRNA) variants was examined using 5' and 3' RACE. In addition to the Npy mRNA species annotated in GenBank and Ensembl, we identified a novel short mRNA splice variant. Immunoblotting results argued against a putative translation of this short mRNA into protein in brain tissue. Compared to the FRL, the FSL had reduced short Npy mRNA levels in the HIP (P = 0.00014) and the PFC (P = 0.016). Gene expression analyses in five brain regions of an outbred rat strain supported the presence of the short Npy transcript in all examined regions and showed that it is expressed in similar to 2.4-fold lower levels than the long Npy mRNA. Finally, sequencing of the 5' RACE products revealed a transcription start site of Npy that is different from the currently annotated position. These data add to the characterization of the rat Npy mRNA and demonstrate the presence of a novel transcript with a so far unknown function.
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