Age-associated DNA methylation changes in immune genes, histone modifiers and chromatin remodeling factors within 5 years after birth in human blood leukocytes

Nathalie Acevedo; Lovisa E Reinius; Morana Vitezic; Vittorio Fortino; Cilla Söderhäll; Hanna Honkanen; Riitta Veijola; Olli Simell; Jorma Toppari; Jorma Ilonen; Mikael Knip; Annika Scheynius; Heikki Hyöty; Dario Greco; Juha Kere

doi:10.1186/s13148-015-0064-6

Age-associated DNA methylation changes in immune genes, histone modifiers and chromatin remodeling factors within 5 years after birth in human blood leukocytes

Nathalie Acevedo, Lovisa E Reinius, Morana Vitezic, Vittorio Fortino, Cilla Söderhäll, Hanna Honkanen, Riitta Veijola, Olli Simell, Jorma Toppari, Jorma Ilonen, Mikael Knip, Annika Scheynius, Heikki Hyöty, Dario Greco, Juha Kere

Computational and RNA Biology

44 Citations (Scopus)

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Abstract

Background: Age-related changes in DNA methylation occurring in blood leukocytes during early childhood may reflect epigenetic maturation. We hypothesized that some of these changes involve gene networks of critical relevance in leukocyte biology and conducted a prospective study to elucidate the dynamics of DNA methylation. Serial blood samples were collected at 3, 6, 12, 24, 36, 48 and 60 months after birth in ten healthy girls born in Finland and participating in the Type 1 Diabetes Prediction and Prevention Study. DNA methylation was measured using the HumanMethylation450 BeadChip. Results: After filtering for the presence of polymorphisms and cell-lineage-specific signatures, 794 CpG sites showed significant DNA methylation differences as a function of age in all children (41.6% age-methylated and 58.4% age-demethylated, Bonferroni-corrected P value <0.01). Age-methylated CpGs were more frequently located in gene bodies and within +5 to +50 kilobases (kb) of transcription start sites (TSS) and enriched in developmental, neuronal and plasma membrane genes. Age-demethylated CpGs were associated to promoters and DNAse-I hypersensitivity sites, located within −5 to +5 kb of the nearest TSS and enriched in genes related to immunity, antigen presentation, the polycomb-group protein complex and cytoplasm. Conclusions: This study reveals that susceptibility loci for complex inflammatory diseases (for example, IRF5, NOD2, and PTGER4) and genes encoding histone modifiers and chromatin remodeling factors (for example, HDAC4, KDM2A, KDM2B, JARID2, ARID3A, and SMARCD3) undergo DNA methylation changes in leukocytes during early childhood. These results open new perspectives to understand leukocyte maturation and provide a catalogue of CpG sites that may need to be corrected for age effects when performing DNA methylation studies in children.

Original language	English
Article number	34
Journal	Clinical Epigenetics
Volume	7
Number of pages	20
ISSN	1868-7075
DOIs	https://doi.org/10.1186/s13148-015-0064-6
Publication status	Published - 2015

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Acevedo, N., Reinius, L. E., Vitezic, M., Fortino, V., Söderhäll, C., Honkanen, H., Veijola, R., Simell, O., Toppari, J., Ilonen, J., Knip, M., Scheynius, A., Hyöty, H., Greco, D., & Kere, J. (2015). Age-associated DNA methylation changes in immune genes, histone modifiers and chromatin remodeling factors within 5 years after birth in human blood leukocytes. Clinical Epigenetics, 7, [34]. https://doi.org/10.1186/s13148-015-0064-6

Acevedo, N, Reinius, LE, Vitezic, M, Fortino, V, Söderhäll, C, Honkanen, H, Veijola, R, Simell, O, Toppari, J, Ilonen, J, Knip, M, Scheynius, A, Hyöty, H, Greco, D & Kere, J 2015, 'Age-associated DNA methylation changes in immune genes, histone modifiers and chromatin remodeling factors within 5 years after birth in human blood leukocytes', Clinical Epigenetics, vol. 7, 34. https://doi.org/10.1186/s13148-015-0064-6

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title = "Age-associated DNA methylation changes in immune genes, histone modifiers and chromatin remodeling factors within 5 years after birth in human blood leukocytes",

abstract = "Background: Age-related changes in DNA methylation occurring in blood leukocytes during early childhood may reflect epigenetic maturation. We hypothesized that some of these changes involve gene networks of critical relevance in leukocyte biology and conducted a prospective study to elucidate the dynamics of DNA methylation. Serial blood samples were collected at 3, 6, 12, 24, 36, 48 and 60 months after birth in ten healthy girls born in Finland and participating in the Type 1 Diabetes Prediction and Prevention Study. DNA methylation was measured using the HumanMethylation450 BeadChip. Results: After filtering for the presence of polymorphisms and cell-lineage-specific signatures, 794 CpG sites showed significant DNA methylation differences as a function of age in all children (41.6% age-methylated and 58.4% age-demethylated, Bonferroni-corrected P value <0.01). Age-methylated CpGs were more frequently located in gene bodies and within +5 to +50 kilobases (kb) of transcription start sites (TSS) and enriched in developmental, neuronal and plasma membrane genes. Age-demethylated CpGs were associated to promoters and DNAse-I hypersensitivity sites, located within −5 to +5 kb of the nearest TSS and enriched in genes related to immunity, antigen presentation, the polycomb-group protein complex and cytoplasm. Conclusions: This study reveals that susceptibility loci for complex inflammatory diseases (for example, IRF5, NOD2, and PTGER4) and genes encoding histone modifiers and chromatin remodeling factors (for example, HDAC4, KDM2A, KDM2B, JARID2, ARID3A, and SMARCD3) undergo DNA methylation changes in leukocytes during early childhood. These results open new perspectives to understand leukocyte maturation and provide a catalogue of CpG sites that may need to be corrected for age effects when performing DNA methylation studies in children.",

author = "Nathalie Acevedo and Reinius, {Lovisa E} and Morana Vitezic and Vittorio Fortino and Cilla S{\"o}derh{\"a}ll and Hanna Honkanen and Riitta Veijola and Olli Simell and Jorma Toppari and Jorma Ilonen and Mikael Knip and Annika Scheynius and Heikki Hy{\"o}ty and Dario Greco and Juha Kere",

year = "2015",

doi = "10.1186/s13148-015-0064-6",

language = "English",

volume = "7",

journal = "Clinical Epigenetics (Print)",

issn = "1868-7075",

publisher = "BioMed Central Ltd.",

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TY - JOUR

T1 - Age-associated DNA methylation changes in immune genes, histone modifiers and chromatin remodeling factors within 5 years after birth in human blood leukocytes

AU - Acevedo, Nathalie

AU - Reinius, Lovisa E

AU - Vitezic, Morana

AU - Fortino, Vittorio

AU - Söderhäll, Cilla

AU - Honkanen, Hanna

AU - Veijola, Riitta

AU - Simell, Olli

AU - Toppari, Jorma

AU - Ilonen, Jorma

AU - Knip, Mikael

AU - Scheynius, Annika

AU - Hyöty, Heikki

AU - Greco, Dario

AU - Kere, Juha

PY - 2015

Y1 - 2015

N2 - Background: Age-related changes in DNA methylation occurring in blood leukocytes during early childhood may reflect epigenetic maturation. We hypothesized that some of these changes involve gene networks of critical relevance in leukocyte biology and conducted a prospective study to elucidate the dynamics of DNA methylation. Serial blood samples were collected at 3, 6, 12, 24, 36, 48 and 60 months after birth in ten healthy girls born in Finland and participating in the Type 1 Diabetes Prediction and Prevention Study. DNA methylation was measured using the HumanMethylation450 BeadChip. Results: After filtering for the presence of polymorphisms and cell-lineage-specific signatures, 794 CpG sites showed significant DNA methylation differences as a function of age in all children (41.6% age-methylated and 58.4% age-demethylated, Bonferroni-corrected P value <0.01). Age-methylated CpGs were more frequently located in gene bodies and within +5 to +50 kilobases (kb) of transcription start sites (TSS) and enriched in developmental, neuronal and plasma membrane genes. Age-demethylated CpGs were associated to promoters and DNAse-I hypersensitivity sites, located within −5 to +5 kb of the nearest TSS and enriched in genes related to immunity, antigen presentation, the polycomb-group protein complex and cytoplasm. Conclusions: This study reveals that susceptibility loci for complex inflammatory diseases (for example, IRF5, NOD2, and PTGER4) and genes encoding histone modifiers and chromatin remodeling factors (for example, HDAC4, KDM2A, KDM2B, JARID2, ARID3A, and SMARCD3) undergo DNA methylation changes in leukocytes during early childhood. These results open new perspectives to understand leukocyte maturation and provide a catalogue of CpG sites that may need to be corrected for age effects when performing DNA methylation studies in children.

AB - Background: Age-related changes in DNA methylation occurring in blood leukocytes during early childhood may reflect epigenetic maturation. We hypothesized that some of these changes involve gene networks of critical relevance in leukocyte biology and conducted a prospective study to elucidate the dynamics of DNA methylation. Serial blood samples were collected at 3, 6, 12, 24, 36, 48 and 60 months after birth in ten healthy girls born in Finland and participating in the Type 1 Diabetes Prediction and Prevention Study. DNA methylation was measured using the HumanMethylation450 BeadChip. Results: After filtering for the presence of polymorphisms and cell-lineage-specific signatures, 794 CpG sites showed significant DNA methylation differences as a function of age in all children (41.6% age-methylated and 58.4% age-demethylated, Bonferroni-corrected P value <0.01). Age-methylated CpGs were more frequently located in gene bodies and within +5 to +50 kilobases (kb) of transcription start sites (TSS) and enriched in developmental, neuronal and plasma membrane genes. Age-demethylated CpGs were associated to promoters and DNAse-I hypersensitivity sites, located within −5 to +5 kb of the nearest TSS and enriched in genes related to immunity, antigen presentation, the polycomb-group protein complex and cytoplasm. Conclusions: This study reveals that susceptibility loci for complex inflammatory diseases (for example, IRF5, NOD2, and PTGER4) and genes encoding histone modifiers and chromatin remodeling factors (for example, HDAC4, KDM2A, KDM2B, JARID2, ARID3A, and SMARCD3) undergo DNA methylation changes in leukocytes during early childhood. These results open new perspectives to understand leukocyte maturation and provide a catalogue of CpG sites that may need to be corrected for age effects when performing DNA methylation studies in children.

U2 - 10.1186/s13148-015-0064-6

DO - 10.1186/s13148-015-0064-6

M3 - Journal article

C2 - 25874017

SN - 1868-7075

VL - 7

JO - Clinical Epigenetics (Print)

JF - Clinical Epigenetics (Print)

M1 - 34

ER -

Age-associated DNA methylation changes in immune genes, histone modifiers and chromatin remodeling factors within 5 years after birth in human blood leukocytes

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