The emerging landscape of dynamic DNA methylation in early childhood

Cheng-Jian Xu; Marc Jan Bonder; Cilla Söderhäll; Mariona Bustamante; Nour Baïz; Ulrike Gehring; Soesma A Jankipersadsing; Pieter Van Der Vlies; Cleo C van Diemen; Bianca van Rijkom; Jocelyne Just; Inger Kull; Juha Kere; Josep Maria Antó; Jean Bousquet; Alexandra Zhernakova; Cisca Wijmenga; Isabella Annesi-Maesano; Jordi Sunyer; Erik Melén; Yang Li; Dirkje S Postma; Gerard H Koppelman

doi:10.1186/s12864-016-3452-1

The emerging landscape of dynamic DNA methylation in early childhood

Cheng-Jian Xu, Marc Jan Bonder, Cilla Söderhäll, Mariona Bustamante, Nour Baïz, Ulrike Gehring, Soesma A Jankipersadsing, Pieter Van Der Vlies, Cleo C van Diemen, Bianca van Rijkom, Jocelyne Just, Inger Kull, Juha Kere, Josep Maria Antó, Jean Bousquet, Alexandra Zhernakova, Cisca Wijmenga, Isabella Annesi-Maesano, Jordi Sunyer, Erik MelénYang Li, Dirkje S Postma, Gerard H Koppelman

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. [email protected].
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
Epidemiology of Allergic and Respiratory Diseases Department (EPAR), Sorbonne Université, UPMC Univ Paris 06, INSERM, Pierre Louis Institute of Epidemiology and Public Health, Saint-Antoine Medical School, Paris, France.
Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, The Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Allergology-Centre de l'Asthme et des Allergies, Hôpital d'Enfants Armand Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France.
Department of Clinical Science and Education, Stockholm South General Hospital, Karolinska Institutet, and Sachs' Children's Hospital, SE-118 83, Stockholm, Sweden.
Folkhälsan Institute of Genetics and Research Programs Unit, University of Helsinki, Helsinki, Finland.
IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
UVSQ, UMR-S 1168, Université Versailles St-Quentin-en-Yvelines, Versailles, France.
Department of Paediatric Pulmonology and Paediatric Allergy, Beatrix Children's Hospital, GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. [email protected].
University of Groningen, University Medical Center Groningen, Department of Paediatric Pulmonology and Paediatric Allergology, Beatrix Children's Hospital, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands.
Department of Paediatric Pulmonology and Paediatric Allergy, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, GRIAC Research Institute, Groningen, The Netherlands.

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND: DNA methylation has been found to associate with disease, aging and environmental exposure, but it is unknown how genome, environment and disease influence DNA methylation dynamics in childhood.

RESULTS: By analysing 538 paired DNA blood samples from children at birth and at 4-5 years old and 726 paired samples from children at 4 and 8 years old from four European birth cohorts using the Illumina Infinium Human Methylation 450 k chip, we have identified 14,150 consistent age-differential methylation sites (a-DMSs) at epigenome-wide significance of p < 1.14 × 10-7. Genes with an increase in age-differential methylation were enriched in pathways related to 'development', and were more often located in bivalent transcription start site (TSS) regions, which can silence or activate expression of developmental genes. Genes with a decrease in age-differential methylation were involved in cell signalling, and enriched on H3K27ac, which can predict developmental state. Maternal smoking tended to decrease methylation levels at the identified da-DMSs. We also found 101 a-DMSs (0.71%) that were regulated by genetic variants using cis-differential Methylation Quantitative Trait Locus (cis-dMeQTL) mapping. Moreover, a-DMS-associated genes during early development were significantly more likely to be linked with disease.

CONCLUSION: Our study provides new insights into the dynamic epigenetic landscape of the first 8 years of life.

Original language	English
Article number	25
Number of pages	11
Journal	BMC Genomics
Volume	18
Issue number	1
DOIs	https://doi.org/10.1186/s12864-016-3452-1
Publication status	Published - 5 Jan 2017

Keywords

Child
Child Development
Child, Preschool
CpG Islands
DNA Methylation
Epigenesis, Genetic
Epigenomics
Female
Genetic Predisposition to Disease
Genetic Variation
Genome-Wide Association Study
Humans
Infant
Infant, Newborn
Maternal Exposure
Pregnancy
Prenatal Exposure Delayed Effects
Quantitative Trait Loci
Smoking
Journal Article
Research Support, Non-U.S. Gov't

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Xu, C.-J., Bonder, M. J., Söderhäll, C., Bustamante, M., Baïz, N., Gehring, U., Jankipersadsing, S. A., Van Der Vlies, P., van Diemen, C. C., van Rijkom, B., Just, J., Kull, I., Kere, J., Antó, J. M., Bousquet, J., Zhernakova, A., Wijmenga, C., Annesi-Maesano, I., Sunyer, J., ... Koppelman, G. H. (2017). The emerging landscape of dynamic DNA methylation in early childhood. BMC Genomics, 18(1), Article 25. https://doi.org/10.1186/s12864-016-3452-1

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abstract = "BACKGROUND: DNA methylation has been found to associate with disease, aging and environmental exposure, but it is unknown how genome, environment and disease influence DNA methylation dynamics in childhood.RESULTS: By analysing 538 paired DNA blood samples from children at birth and at 4-5 years old and 726 paired samples from children at 4 and 8 years old from four European birth cohorts using the Illumina Infinium Human Methylation 450 k chip, we have identified 14,150 consistent age-differential methylation sites (a-DMSs) at epigenome-wide significance of p < 1.14 × 10-7. Genes with an increase in age-differential methylation were enriched in pathways related to 'development', and were more often located in bivalent transcription start site (TSS) regions, which can silence or activate expression of developmental genes. Genes with a decrease in age-differential methylation were involved in cell signalling, and enriched on H3K27ac, which can predict developmental state. Maternal smoking tended to decrease methylation levels at the identified da-DMSs. We also found 101 a-DMSs (0.71%) that were regulated by genetic variants using cis-differential Methylation Quantitative Trait Locus (cis-dMeQTL) mapping. Moreover, a-DMS-associated genes during early development were significantly more likely to be linked with disease.CONCLUSION: Our study provides new insights into the dynamic epigenetic landscape of the first 8 years of life.",

keywords = "Child, Child Development, Child, Preschool, CpG Islands, DNA Methylation, Epigenesis, Genetic, Epigenomics, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Infant, Infant, Newborn, Maternal Exposure, Pregnancy, Prenatal Exposure Delayed Effects, Quantitative Trait Loci, Smoking, Journal Article, Research Support, Non-U.S. Gov't",

author = "Cheng-Jian Xu and Bonder, {Marc Jan} and Cilla S{\"o}derh{\"a}ll and Mariona Bustamante and Nour Ba{\"i}z and Ulrike Gehring and Jankipersadsing, {Soesma A} and {Van Der Vlies}, Pieter and {van Diemen}, {Cleo C} and {van Rijkom}, Bianca and Jocelyne Just and Inger Kull and Juha Kere and Ant{\'o}, {Josep Maria} and Jean Bousquet and Alexandra Zhernakova and Cisca Wijmenga and Isabella Annesi-Maesano and Jordi Sunyer and Erik Mel{\'e}n and Yang Li and Postma, {Dirkje S} and Koppelman, {Gerard H}",

year = "2017",

month = jan,

day = "5",

doi = "10.1186/s12864-016-3452-1",

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Xu, C-J, Bonder, MJ, Söderhäll, C, Bustamante, M, Baïz, N, Gehring, U, Jankipersadsing, SA, Van Der Vlies, P, van Diemen, CC, van Rijkom, B, Just, J, Kull, I, Kere, J, Antó, JM, Bousquet, J, Zhernakova, A, Wijmenga, C, Annesi-Maesano, I, Sunyer, J, Melén, E, Li, Y, Postma, DS & Koppelman, GH 2017, 'The emerging landscape of dynamic DNA methylation in early childhood', BMC Genomics, vol. 18, no. 1, 25. https://doi.org/10.1186/s12864-016-3452-1

TY - JOUR

T1 - The emerging landscape of dynamic DNA methylation in early childhood

AU - Xu, Cheng-Jian

AU - Bonder, Marc Jan

AU - Söderhäll, Cilla

AU - Bustamante, Mariona

AU - Baïz, Nour

AU - Gehring, Ulrike

AU - Jankipersadsing, Soesma A

AU - Van Der Vlies, Pieter

AU - van Diemen, Cleo C

AU - van Rijkom, Bianca

AU - Just, Jocelyne

AU - Kull, Inger

AU - Kere, Juha

AU - Antó, Josep Maria

AU - Bousquet, Jean

AU - Zhernakova, Alexandra

AU - Wijmenga, Cisca

AU - Annesi-Maesano, Isabella

AU - Sunyer, Jordi

AU - Melén, Erik

AU - Li, Yang

AU - Postma, Dirkje S

AU - Koppelman, Gerard H

PY - 2017/1/5

Y1 - 2017/1/5

N2 - BACKGROUND: DNA methylation has been found to associate with disease, aging and environmental exposure, but it is unknown how genome, environment and disease influence DNA methylation dynamics in childhood.RESULTS: By analysing 538 paired DNA blood samples from children at birth and at 4-5 years old and 726 paired samples from children at 4 and 8 years old from four European birth cohorts using the Illumina Infinium Human Methylation 450 k chip, we have identified 14,150 consistent age-differential methylation sites (a-DMSs) at epigenome-wide significance of p < 1.14 × 10-7. Genes with an increase in age-differential methylation were enriched in pathways related to 'development', and were more often located in bivalent transcription start site (TSS) regions, which can silence or activate expression of developmental genes. Genes with a decrease in age-differential methylation were involved in cell signalling, and enriched on H3K27ac, which can predict developmental state. Maternal smoking tended to decrease methylation levels at the identified da-DMSs. We also found 101 a-DMSs (0.71%) that were regulated by genetic variants using cis-differential Methylation Quantitative Trait Locus (cis-dMeQTL) mapping. Moreover, a-DMS-associated genes during early development were significantly more likely to be linked with disease.CONCLUSION: Our study provides new insights into the dynamic epigenetic landscape of the first 8 years of life.

AB - BACKGROUND: DNA methylation has been found to associate with disease, aging and environmental exposure, but it is unknown how genome, environment and disease influence DNA methylation dynamics in childhood.RESULTS: By analysing 538 paired DNA blood samples from children at birth and at 4-5 years old and 726 paired samples from children at 4 and 8 years old from four European birth cohorts using the Illumina Infinium Human Methylation 450 k chip, we have identified 14,150 consistent age-differential methylation sites (a-DMSs) at epigenome-wide significance of p < 1.14 × 10-7. Genes with an increase in age-differential methylation were enriched in pathways related to 'development', and were more often located in bivalent transcription start site (TSS) regions, which can silence or activate expression of developmental genes. Genes with a decrease in age-differential methylation were involved in cell signalling, and enriched on H3K27ac, which can predict developmental state. Maternal smoking tended to decrease methylation levels at the identified da-DMSs. We also found 101 a-DMSs (0.71%) that were regulated by genetic variants using cis-differential Methylation Quantitative Trait Locus (cis-dMeQTL) mapping. Moreover, a-DMS-associated genes during early development were significantly more likely to be linked with disease.CONCLUSION: Our study provides new insights into the dynamic epigenetic landscape of the first 8 years of life.

KW - Child

KW - Child Development

KW - Child, Preschool

KW - CpG Islands

KW - DNA Methylation

KW - Epigenesis, Genetic

KW - Epigenomics

KW - Female

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Maternal Exposure

KW - Pregnancy

KW - Prenatal Exposure Delayed Effects

KW - Quantitative Trait Loci

KW - Smoking

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1186/s12864-016-3452-1

DO - 10.1186/s12864-016-3452-1

M3 - Article

C2 - 28056824

SN - 1471-2164

VL - 18

JO - BMC Genomics

JF - BMC Genomics

IS - 1

M1 - 25

ER -

The emerging landscape of dynamic DNA methylation in early childhood

Abstract

Keywords

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