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PLoS One. 2014 Apr 17;9(4):e94555. doi: 10.1371/journal.pone.0094555. eCollection 2014.

Genetic control of differential acetylation in diabetic rats.

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The Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford, United Kingdom.
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
INSERM, U872, Cordeliers Research Centre, Paris, France; Institute of Cardiometabolism & Nutrition, ICAN, Pitié-Salpêtrière Hospital, University Pierre & Marie-Curie, Paris, France.
National Genotyping Centre, Evry, France.


Post-translational protein modifications such as acetylation have significant regulatory roles in metabolic processes, but their relationship to both variation in gene expression and DNA sequence is unclear. We address this question in the Goto-Kakizaki (GK) rat inbred strain, a model of polygenic type 2 diabetes. Expression of the NAD-dependent deacetylase Sirtuin-3 is down-regulated in GK rats compared to normoglycemic Brown Norway (BN) rats. We show first that a promoter SNP causes down-regulation of Sirtuin-3 expression in GK rats. We then use mass-spectrometry to identify proteome-wide differential lysine acetylation of putative Sirtuin-3 protein targets in livers of GK and BN rats. These include many proteins in pathways connected to diabetes and metabolic syndrome. We finally sequence GK and BN liver transcriptomes and find that mRNA expression of these targets does not differ significantly between GK and BN rats, in contrast to other components of the same pathways. We conclude that physiological differences between GK and BN rats are mediated by a combination of differential protein acetylation and gene transcription and that genetic variation can modulate acetylation independently of expression.

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