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Bioinformatic and Biostatitic Analysis of Epigenetic Data from Humans and Mice in the Context of Obesity and Its Complications Sarah Voisin

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Bioinformatic and Biostatitic Analysis of Epigenetic Data from Humans and Mice in the Context of Obesity and Its Complications Sarah Voisin Bioinformatic and biostatitic analysis of epigenetic data from humans and mice in the context of obesity and its complications Sarah Voisin To cite this version: Sarah Voisin. Bioinformatic and biostatitic analysis of epigenetic data from humans and mice in the context of obesity and its complications. Development Biology. Université Pierre et Marie Curie - Paris 6; Uppsala University, 2016. English. tel-02800507 HAL Id: tel-02800507 https://hal.inrae.fr/tel-02800507 Submitted on 5 Jun 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1245 Bioinformatic and Biostatistic Analysis of Epigenetic Data from Humans and Mice in the Context of Obesity and its Complications SARAH VOISIN ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 UPPSALA ISBN 978-91-554-9655-5 2016 urn:nbn:se:uu:diva-300751 Dissertation presented at Uppsala University to be publicly examined in Uppsala, Thursday, 22 September 2016 at 13:00 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in English. Faculty examiner: Associate professor Romain Barres (Section for Integrative Physiology, University of Copenhagen, Denmark). Abstract Voisin, S. 2016. Bioinformatic and Biostatistic Analysis of Epigenetic Data from Humans and Mice in the Context of Obesity and its Complications. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1245. 219 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9655-5. Worldwide obesity has more than doubled since 1980 and at least 2.8 million people die each year as a result of being overweight or obese. An elevated body weight is the result of the interplay between susceptibility gene variants and an obesogenic environment, and recent evidence shows that epigenetic processes are likely involved. The growing availability of high- throughput technologies has made it possible to assess quickly the entire epigenome of large samples at a relatively low cost. As a result, vast amounts of data have been generated and researchers are now confronted to both bioinformatic and biostatistic challenges to make sense of such data in the context of obesity and its complications. In this doctoral thesis, we explored associations between the human blood methylome and obesity-associated gene variants as well as dietary fat quality and quantity. We used well described preprocessing techniques and statistical methods, along with publicly available data from consortiums and other research groups, as well as tools for pathway enrichment and chromatin state inference. We found associations between obesityassociated SNPs and methylation levels at proximal promoters and enhancers, and some of these associations were replicated in multiple tissues. We also found that contrary to dietary fat quantity, dietary fat quality associates with methylation levels in the promoter of genes involved in metabolic pathways. Then, using a gene-targeted approach, we looked at the impact of an acute environmental stress (sleep loss) on the methylation and transcription levels of circadian clock genes in skeletal muscle and adipose tissue of healthy men. We found that a single night of wakefulness can alter the epigenetic and transcriptional profile of core circadian clock genes in a tissue-specific manner. Finally, we looked at the effects of chronic maternal obesity and subsequent weight loss on the transcription of epigenetic machinery genes in the fetus and placenta of mice. We found that the transcription of epigenetic machinery genes is highly sensitive to maternal weight trajectories, and particularly those of the histone acetylation pathway. Overall, this thesis demonstrated that genetics, obesogenic environment stimuli and maternal programming impact epigenetic marks at genomic locations relevant in the pathogenesis of obesity. Keywords: obesity, genetics, epigenetics, DNA methylation, sleep, developmental origins of health and disease, single nucleotide polymorphism, genome-wide association study Sarah Voisin, , Department of Neuroscience, Box 593, Uppsala University, SE-75124 Uppsala, Sweden. © Sarah Voisin 2016 ISSN 1651-6206 ISBN 978-91-554-9655-5 urn:nbn:se:uu:diva-300751 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-300751) An apple a day will keep anyone away if thrown hard enough. Unknown If your experiment needs statistics, you ought to do a better experiment. Lord Ernest Rutherford List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Voisin S, Almén MS, Zheleznyakova GY, Lundberg L, Zarei S, Castillo S, Eriksson FE, Nilsson EK, Blüher M, Böttcher Y, Kovacs P, Klovins J, Rask-Andersen M, Schiöth HB, Many obesity-associated SNPs strongly associate with DNA methylation changes at proximal promoters and enhancers, Genome Medicine 2015, 7:103. II Voisin S, Almén MS, Moschonis G, Chrousos GP, Manios Y, Schiöth HB, Dietary fat quality impacts genome-wide DNA methylation patterns in a cross-sectional study of Greek preadolescents, Eur J Hum Genet 2014, 23(5): 654-662 III Cedernaes J, Osler ME, Voisin S, Broman JE, Vogel H, Dickson SL, Zierath JR, Schiöth HB, Benedict C, Acute sleep loss induces tissue-specific epigenetic and transcriptional al- terations to circadian clock genes in men, J Clin Endocrinol Metab 2015, 100(9): E1255– E1261 IV Panchenko PE, Voisin S, Jouin M, Jouneau L, Prezelin A, Lecoutre S, Breton C, Jammes H, Junien C, Gabory A, Expression of epigenetic machinery genes is sensitive to maternal obesity and weight loss in relation to fetal growth, Clinical Epigenetics 2016, 8(22). Reprints were made with permission from the respective publishers. Additional publications ñ Voisin S, Guilherme JPFL, Yan X, Pushkarev VP, Cieszczyk P, Massidda M, et al. ACVR1B rs2854464 Is Associated with Sprint/Power Athletic Status in a Large Cohort of Europeans but Not Brazilians. PLoS One. United States; 2016;11: e0156316. doi:10.1371/journal.pone.0156316 ñ Voisin S, Cieszczyk P, Pushkarev VP, Dyatlov DA, Vashlyayev BF, Shumaylov VA, Maciejewska-Karlowska A, Sawczuk M, Skuza L, Jastrzebski Z, Bishop DJ, Eynon N, EPAS1 gene variants are associated with sprint/power athletic performance in two cohorts of European athletes, BMC Genomics, 15(1): 382 ñ Voisin S, Eynon N, Yan X, Bishop DJ, Exercise training and DNA methylation in humans, Acta Physiol (Oxf) 2015, 213(1): 39–59 ñ Yang R, Shen X, Wang Y, Voisin S, Cai G, Fu Y, et al. ACTN3 R577X Gene Variant is Associated with Muscle-related Phenotypes in elite Chinese Sprint/Power Athletes. J strength Cond Res / Natl Strength Cond Assoc. 2016; doi:10.1519/JSC.0000000000001558 ñ Williams MJ, Klockars A, Eriksson A, Wiemerslage L, Voisin S, Dnyansagar R, Kasagiannis A, Ambrosi A, Fredriksson R , Schiöth HB, The Drosophila ETV5 homologue Ets96B: Molecular link between obesity and bipolar disorder, PLoS Genetics 2016 ñ Boström AE, Mwinyi J, Benedict C, Voisin S, Wu W, Schultes B, Zhang K, Schiöth HB, Longitudinal genome-wide methylation study of Roux-en-Y gastric bypass patients reveals novel CpG sites associated with essential hypertension, BMC Medical Genomics 2016, 9(20). ñ Bandstein M, Voisin S, Nilsson EK, Schultes B, Ernst B, Thurnheer M, Benedict C, Mwinyi J, Schiöth HB, A genetic risk score is associated with weight loss following Roux- Y gastric bypass surgery, Obesity Surgery 2016 ñ Williams MJ, Eriksson A, Shaik M, Voisin S, Yamskova O, Paulsson J, Thombare K, Fredriksson R, Schiöth HB, The obesity-linked gene Nudt3 Drosophila homolog Aps is as- sociated with insulin signalling, Mol Endocrinol 2015, 29(9): 1303–1319. ñ Banerjee HN, Banerji A, Banerjee AN, Riddick E, Petis J, Evans S, Patel M, Parson C, Smith V, Gwebu E, Voisin S, Deciphering the Finger Prints of Brain Cancer Glioblastoma Multiforme from Four Different Patients by Using Near Infrared Raman Spectroscopy. J Cancer Sci Ther 2015, 7(2): 44–47. ñ Eriksson A, Williams MJ, Voisin S, Hansson I, Krishnan A, Philippot G, Yamskova O, Herisson FM, Dnyansagar R, Moschonis G, Manios Y, Chrousos GP, Olszewski PK, Frediksson R, Schiöth HB, Implication of coronin 7 in body weight regulation in humans, mice and flies, BMC Neurosci 2015, 16(1): 13. ñ Nilsson EK, Ernst B, Voisin S, Almén MS, Benedict C, Mwinyi J, Fredriksson R, Schultes B, Schiöth HB, Roux-en Y gastric bypass surgery induces genome-wide promoter-specific changes in DNA methylation in whole blood of obese patients, PLoS One 2015, 10(2): e0115186. ñ Ségurel L, Austerlitz F, Toupance B, Gautier M, Kelley JL, Pasquet P, Lonjou C, Georges M, Voisin S, Cruaud C, Couloux A, Hegay T, Aldashev A, Vitalis R, Heyer E, Positive se- lection of protective variants for type 2 diabetes from the Neolithic onward: a case study in Central Asia, Eur J Hum Genet 2013 21(10): 1146–51. ñ Zheleznyakova GY, Voisin S, Kiselev AV, Almén MS, Xavier MJ, Maretina MA, Tishchenko LI, Fredriksson R, Baranov VS, Schiöth HB, Genome-wide analysis shows as- sociation of epigenetic changes in regulators of
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