The anxiety and ethanol intake controlling GAL5.1 enhancer is epigenetically modulated by, and controls preference for,
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
The anxiety and ethanol intake controlling GAL5.1 enhancer is epigenetically modulated by, and controls preference for, high‑fat diet Andrew McEwan1 · Johanna Celene Erickson1 · Connor Davidson1 · Jenny Heijkoop1 · Yvonne Turnbull1 · Mirela Delibegovic1 · Christopher Murgatroyd2 · Alasdair MacKenzie1 Received: 25 May 2020 / Revised: 28 October 2020 / Accepted: 6 November 2020 © The Author(s) 2020
Abstract Excess maternal fat intake and obesity increase offspring susceptibility to conditions such as chronic anxiety and substance abuse. We hypothesised that environmentally modulated DNA methylation changes (5mC/5hmC) in regulatory regions of the genome that modulate mood and consumptive behaviours could contribute to susceptibility to these conditions. We explored the effects of environmental factors on 5mC/5hmC levels within the GAL5.1 enhancer that controls anxiety-related behaviours and alcohol intake. We first observed that 5mC/5hmC levels within the GAL5.1 enhancer differed significantly in different parts of the brain. Moreover, we noted that early life stress had no significant effect of 5mC/5hmC levels within GAL5.1. In contrast, we identified that allowing access of pregnant mothers to high-fat diet (> 60% calories from fat) had a significant effect on 5mC/5hmC levels within GAL5.1 in hypothalamus and amygdala of resulting male offspring. Cell transfection-based studies using GAL5.1 reporter plasmids showed that 5mC has a significant repressive effect on GAL5.1 activity and its response to known stimuli, such as EGR1 transcription factor expression and PKC agonism. Intriguingly, CRISPR-driven disruption of GAL5.1 from the mouse genome, although having negligible effects on metabolism or general appetite, significantly decreased intake of high-fat diet suggesting that GAL5.1, in addition to being epigenetically modulated by high-fat diet, also actively contributes to the consumption of high-fat diet suggesting its involvement in an environmentally influenced regulatory loop. Furthermore, considering that GAL5.1 also controls alcohol preference and anxiety these studies may provide a first glimpse into an epigenetically controlled mechanism that links maternal high-fat diet with transgenerational susceptibility to alcohol abuse and anxiety. Keywords GAL5.1 enhancer sequence · CRISPR genome editing · Galanin · EGR1 · Protein Kinase C · Gene regulation · 5mC/5hmC content · Early life stress · Fat preference · Anxiety and substance abuse
Background
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-020-03705-6) contains supplementary material, which is available to authorized users. * Alasdair MacKenzie [email protected] 1
School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK
Manchester Metropolitan University, Manchester, UK
2
In addition to their acute involvement in obesity [1, 2] there is
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