title: Genetic control of differential acetylation in diabetic rats.
abstract: 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.
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford, United Kingdom.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Kaisaki
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford, United Kingdom.
authors.forename: Georg W
authors.initials: GW
authors.lastname: Otto
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Joanna F
authors.initials: JF
authors.lastname: McGouran
authors.affiliation: INSERM, U872, Cordeliers Research Centre, Paris, France; Institute of Cardiometabolism & Nutrition, ICAN, Pitié-Salpêtrière Hospital, University Pierre & Marie-Curie, Paris, France.
authors.forename: Amine
authors.initials: A
authors.lastname: Toubal
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford, United Kingdom.
authors.forename: Karène
authors.initials: K
authors.lastname: Argoud
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Waller-Evans
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford, United Kingdom.
authors.forename: Clare
authors.initials: C
authors.lastname: Finlay
authors.affiliation: INSERM, U872, Cordeliers Research Centre, Paris, France; Institute of Cardiometabolism & Nutrition, ICAN, Pitié-Salpêtrière Hospital, University Pierre & Marie-Curie, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Caldérari
authors.affiliation: National Genotyping Centre, Evry, France.
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Bihoreau
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Benedikt M
authors.initials: BM
authors.lastname: Kessler
authors.affiliation: INSERM, U872, Cordeliers Research Centre, Paris, France; Institute of Cardiometabolism & Nutrition, ICAN, Pitié-Salpêtrière Hospital, University Pierre & Marie-Curie, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Gauguier
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Mott
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000235:genetics; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002952:Citric Acid Cycle; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D005943:Gluconeogenesis; D006019:Glycolysis; D008099:Liver / Q000378:metabolism; D008297:Male; D010427:Pentose Phosphate Pathway; D011110:Polymorphism, Genetic; D011499:Protein Processing, Post-Translational; D040901:Proteomics; D011687:Purines / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism; D051381:Rats; D017423:Sequence Analysis, RNA; D056566:Sirtuin 3 / Q000235:genetics; D013045:Species Specificity; D014158:Transcription, Genetic
chemical_list: D000596:Amino Acids; D005227:Fatty Acids; D011687:Purines; D011743:Pyrimidines; D000123:Acetyltransferases; D056566:Sirtuin 3; C030986:pyrimidine; C030985:purine
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