The anxiety and ethanol intake controlling GAL5.1 enhancer is epigenetically modulated by, and controls preference for, high-fat diet

Andrew McEwan, Johanna Celene Erickson, Connor Davidson, Jenny Heijkoop, Yvonne Turnbull, Mirela Delibegovic, Christopher Murgatroyd , Alasdair MacKenzie* (Corresponding Author)

*Corresponding author for this work

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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.

Original languageEnglish
Pages (from-to)3045-3055
Number of pages11
JournalCellular and Molecular Life Sciences
Issue number6
Early online date12 Dec 2020
Publication statusPublished - Mar 2021

Bibliographical note

Open Access via the Springer Compact Agreement
AMcE, AMcK and CM were funded by BBSRC project grant (BB/N017544/1) and Tenovus Scotland Grampian (award G19.08). We thank all of the staff at the Medical Research Facility for their help and excellent advice in the completion of these studies. We also thank Giuseppe D'agostino for guidence and help through the study.


  • 5mC/5hmC content
  • Anxiety and substance abuse
  • CRISPR genome editing
  • Early life stress
  • EGR1
  • Fat preference
  • GAL5.1 enhancer sequence
  • Galanin
  • Gene regulation
  • Protein Kinase C


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