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Bioinformatic and Biostatistic Analysis of Epigenetic Data from Humans and Mice in the Context of Obesity and its Complications
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Biologie du Developpement et Reproduction, INRA, Jouy-en-Josas. (Functional Pharmacology)
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 143 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1245
Keyword [en]
obesity, genetics, epigenetics, DNA methylation, sleep, developmental origins of health and disease, single nucleotide polymorphism, genome-wide association study
National Category
Medical Genetics Nutrition and Dietetics Genetics
Identifiers
URN: urn:nbn:se:uu:diva-300751ISBN: 978-91-554-9655-5OAI: oai:DiVA.org:uu-300751DiVA: diva2:952297
Public defence
2016-09-22, C8:301, BMC, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2016-08-31 Created: 2016-08-12 Last updated: 2016-09-21
List of papers
1. Many obesity-associated SNPs strongly associate with DNA methylation changes at proximal promoters and enhancers
Open this publication in new window or tab >>Many obesity-associated SNPs strongly associate with DNA methylation changes at proximal promoters and enhancers
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2015 (English)In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 7, 103Article in journal (Refereed) Published
Abstract [en]

Background: The mechanisms by which genetic variants, such as single nucleotide polymorphisms (SNPs), identified in genome-wide association studies act to influence body mass remain unknown for most of these SNPs, which continue to puzzle the scientific community. Recent evidence points to the epigenetic and chromatin states of the genome as having important roles. Methods: We genotyped 355 healthy young individuals for 52 known obesity-associated SNPs and obtained DNA methylation levels in their blood using the Illumina 450 K BeadChip. Associations between alleles and methylation at proximal cytosine residues were tested using a linear model adjusted for age, sex, weight category, and a proxy for blood cell type counts. For replication in other tissues, we used two open-access datasets (skin fibroblasts, n = 62; four brain regions, n = 121-133) and an additional dataset in subcutaneous and visceral fat (n = 149). Results: We found that alleles at 28 of these obesity-associated SNPs associate with methylation levels at 107 proximal CpG sites. Out of 107 CpG sites, 38 are located in gene promoters, including genes strongly implicated in obesity (MIR148A, BDNF, PTPMT1, NR1H3, MGAT1, SCGB3A1, HOXC12, PMAIP1, PSIP1, RPS10-NUDT3, RPS10, SKOR1, MAP2K5, SIX5, AGRN, IMMP1L, ELP4, ITIH4, SEMA3G, POMC, ADCY3, SSPN, LGR4, TUFM, MIR4721, SULT1A1, SULT1A2, APOBR, CLN3, SPNS1, SH2B1, ATXN2L, and IL27). Interestingly, the associated SNPs are in known eQTLs for some of these genes. We also found that the 107 CpGs are enriched in enhancers in peripheral blood mononuclear cells. Finally, our results indicate that some of these associations are not blood-specific as we successfully replicated four associations in skin fibroblasts. Conclusions: Our results strongly suggest that many obesity-associated SNPs are associated with proximal gene regulation, which was reflected by association of obesity risk allele genotypes with differential DNA methylation. This study highlights the importance of DNA methylation and other chromatin marks as a way to understand the molecular basis of genetic variants associated with human diseases and traits.

National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-265675 (URN)10.1186/s13073-015-0225-4 (DOI)000362476400001 ()26449484 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research CouncilThe Swedish Brain Foundation
Available from: 2015-11-04 Created: 2015-11-02 Last updated: 2016-09-05Bibliographically approved
2. Dietary fat quality impacts genome-wide DNA methylation patterns in a cross-sectional study of Greek preadolescents
Open this publication in new window or tab >>Dietary fat quality impacts genome-wide DNA methylation patterns in a cross-sectional study of Greek preadolescents
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2015 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 23, 654-662 p.Article in journal (Refereed) Published
Abstract [en]

The type and the amount of dietary fat have a significant influence on the metabolic pathways involved in the development of obesity, metabolic syndrome, diabetes type 2 and cardiovascular diseases. However, it is unknown to what extent this modulation is achieved through DNA methylation. We assessed the effects of cholesterol intake, the proportion of energy intake derived from fat, the ratio of polyunsaturated fatty acids (PUFA) to saturated fatty acids (SFA), the ratio of monounsaturated fatty acids (MUFA) to SFA, and the ratio of MUFA+PUFA to SFA on genome-wide DNA methylation patterns in normal-weight and obese children. We determined the genome-wide methylation profile in the blood of 69 Greek preadolescents (∼10 years old) as well as their dietary intake for two consecutive weekdays and one weekend day. The methylation levels of one CpG island shore and four sites were significantly correlated with total fat intake. The methylation levels of 2 islands, 11 island shores and 16 sites were significantly correlated with PUFA/SFA; of 9 islands, 26 island shores and 158 sites with MUFA/SFA; and of 10 islands, 40 island shores and 130 sites with (MUFA+PUFA)/SFA. We found significant gene enrichment in 34 pathways for PUFA/SFA, including the leptin pathway, and a significant enrichment in 5 pathways for (MUFA+PUFA)/SFA. Our results suggest that specific changes in DNA methylation may have an important role in the mechanisms involved in the physiological responses to different types of dietary fat.European Journal of Human Genetics advance online publication, 30 July 2014; doi:10.1038/ejhg.2014.139.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-238744 (URN)10.1038/ejhg.2014.139 (DOI)000353028200018 ()25074463 (PubMedID)
Note

Sarah Voisin och Markus S Almén delar förstaförfattarskapet.

Available from: 2014-12-16 Created: 2014-12-16 Last updated: 2016-09-05Bibliographically approved
3. Expression of epigenetic machinery genes is sensitive to maternal obesity and weight loss in relation to fetal growth in mice
Open this publication in new window or tab >>Expression of epigenetic machinery genes is sensitive to maternal obesity and weight loss in relation to fetal growth in mice
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2016 (English)In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 8, 22Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

Maternal obesity impacts fetal growth and pregnancy outcomes. To counteract the deleterious effects of obesity on fertility and pregnancy issue, preconceptional weight loss is recommended to obese women. Whether this weight loss is beneficial/detrimental for offspring remains poorly explored. Epigenetic mechanisms could be affected by maternal weight changes, perturbing expression of key developmental genes in the placenta or fetus. Our aim was to investigate the effects of chronic maternal obesity on feto-placental growth along with the underlying epigenetic mechanisms. We also tested whether preconceptional weight loss could alleviate these effects.

RESULTS:

Female mice were fed either a control diet (CTRL group), a high-fat diet (obese (OB) group), or a high-fat diet switched to a control diet 2 months before conception (weight loss (WL) group). At mating, OB females presented an obese phenotype while WL females normalized metabolic parameters. At embryonic day 18.5 (E18.5), fetuses from OB females presented fetal growth restriction (FGR; -13 %) and 28 % of the fetuses were small for gestational age (SGA). Fetuses from WL females normalized this phenotype. The expression of 60 epigenetic machinery genes and 32 metabolic genes was measured in the fetal liver, placental labyrinth, and junctional zone. We revealed 23 genes altered by maternal weight trajectories in at least one of three tissues. The fetal liver and placental labyrinth were more responsive to maternal obesity than junctional zone. One third (18/60) of the epigenetic machinery genes were differentially expressed between at least two maternal groups. Interestingly, genes involved in the histone acetylation pathway were particularly altered (13/18). In OB group, lysine acetyltransferases and Bromodomain-containing protein 2 were upregulated, while most histone deacetylases were downregulated. In WL group, the expression of only a subset of these genes was normalized.

CONCLUSIONS:

This study highlights the high sensitivity of the epigenetic machinery gene expression, and particularly the histone acetylation pathway, to maternal obesity. These obesity-induced transcriptional changes could alter the placental and the hepatic epigenome, leading to FGR. Preconceptional weight loss appears beneficial to fetal growth, but some effects of previous obesity were retained in offspring phenotype.

Keyword
Maternal obesity; Preconceptional weight loss; Fetal growth restriction; Epigenetic machinery; Histone deacetylases (HDACs); Lysine acetyltransferases (KATs); Placenta; Liver
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Biology
Identifiers
urn:nbn:se:uu:diva-300748 (URN)10.1186/s13148-016-0188-3 (DOI)000371288600001 ()26925174 (PubMedID)
Available from: 2016-08-12 Created: 2016-08-12 Last updated: 2016-09-05Bibliographically approved
4. Acute Sleep Loss Induces Tissue-Specific Epigenetic and Transcriptional Alterations to Circadian Clock Genes in Men
Open this publication in new window or tab >>Acute Sleep Loss Induces Tissue-Specific Epigenetic and Transcriptional Alterations to Circadian Clock Genes in Men
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2015 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, no 9, E1255-E1261 p.Article in journal (Refereed) Published
Abstract [en]

Context: Shift workers are at increased risk of metabolic morbidities. Clock genes are known to regulate metabolic processes in peripheral tissues, eg, glucose oxidation. Objective: This study aimed to investigate how clock genes are affected at the epigenetic and transcriptional level in peripheral human tissues following acute total sleep deprivation (TSD), mimicking shift work with extended wakefulness. Intervention: In a randomized, two-period, two-condition, crossover clinical study, 15 healthy men underwent two experimental sessions: x sleep (2230-0700 h) and overnight wakefulness. On the subsequent morning, serum cortisol was measured, followed by skeletal muscle and subcutaneous adipose tissue biopsies for DNA methylation and gene expression analyses of core clock genes (8MAL1, CLOCK, CRYT, PERT). Finally, baseline and 2-h post-oral glucose load plasma glucose concentrations were determined. Main Outcome Measures: In adipose tissue, acute sleep deprivation vs sleep increased methylation in the promoter of CRY1 (+4%; P =.026) and in two promoter-interacting enhancer regions of PERT (+15%; P =.036; +9%; P =.026). In skeletal muscle, TSD vs sleep decreased gene expression of BMALT (-18%; P =.033) and CRY1 (-22%; P =.047). Concentrations of serum cortisol, which can reset peripheral tissue clocks, were decreased (2449 932 vs 3178 723 nmol/L; P =.039), whereas postprandial plasma glucose concentrations were elevated after TSD (7.77 1.63 vs 6.59 1.32 mmol/L; P =.011). Conclusions: Our findings demonstrate that a single night of wakefulness can alter the epigenetic and transcriptional profile of core circadian clock genes in key metabolic tissues. Tissue-specific clock alterations could explain why shift work may disrupt metabolic integrity as observed herein.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-269283 (URN)10.1210/jc.2015-2284 (DOI)000364867800024 ()26168277 (PubMedID)
Funder
The Swedish Brain FoundationAFA InsuranceNovo NordiskSwedish Society of MedicineMagnus Bergvall FoundationSwedish Research Council
Available from: 2015-12-15 Created: 2015-12-15 Last updated: 2016-09-05Bibliographically approved

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