title: Allele-specific programming of Npy and epigenetic effects of physical activity in a genetic model of depression.
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.
authors: Department of Molecular Medicine and Surgery, Neurogenetics Unit, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. philippe.melas@ki.se
authors: P A
authors: PA
authors: Melas
authors: A
authors: A
authors: Lennartsson
authors: H
authors: H
authors: Vakifahmetoglu-Norberg
authors: Y
authors: Y
authors: Wei
authors: E
authors: E
authors: Åberg
authors: M
authors: M
authors: Werme
authors: M
authors: M
authors: Rogdaki
authors: M
authors: M
authors: Mannervik
authors: G
authors: G
authors: Wegener
authors: S
authors: S
authors: Brené
authors: A A
authors: AA
authors: Mathé
authors: C
authors: C
authors: Lavebratt
mesh_terms: D000818:Animals; D008192:Deception; D003863:Depression / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000502:physiology*; D015870:Gene Expression / Q000235:genetics / Q000502:physiology; D005838:Genotype; D006624:Hippocampus / Q000737:chemistry / Q000502:physiology; D009043:Motor Activity / Q000502:physiology*; D009478:Neuropeptide Y / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D051381:Rats; D014157:Transcription Factors / Q000502:physiology
chemical_list: D009478:Neuropeptide Y; D014157:Transcription Factors
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