Genome-wide age-related changes in DNA methylation and gene expression in human PBMCs

W.T. Steegenga, M.V. Boekschoten, C. Lute, G.J.E.J. Hooiveld, P.J. de Groot, T.J. Morris, A.E. Teschendorff, L.M. Butcher, S. Beck, M.R. Müller

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Abstract

Aging is a progressive process that results in the accumulation of intra- and extracellular alterations that in turn contribute to a reduction in health. Age-related changes in DNA methylation have been reported before and may be responsible for aging-induced changes in gene expression, although a causal relationship has yet to be shown. Using genome-wide assays, we analyzed age-induced changes in DNA methylation and their effect on gene expression with and without transient induction with the synthetic transcription modulating agent WY14,643. To demonstrate feasibility of the approach, we isolated peripheral blood mononucleated cells (PBMCs) from five young and five old healthy male volunteers and cultured them with or without WY14,643. Infinium 450K BeadChip and Affymetrix Human Gene 1.1 ST expression array analysis revealed significant differential methylation of at least 5 % (¿YO¿>¿5 %) at 10,625 CpG sites between young and old subjects, but only a subset of the associated genes were also differentially expressed. Age-related differential methylation of previously reported epigenetic biomarkers of aging including ELOVL2, FHL2, PENK, and KLF14 was confirmed in our study, but these genes did not display an age-related change in gene expression in PBMCs. Bioinformatic analysis revealed that differentially methylated genes that lack an age-related expression change predominantly represent genes involved in carcinogenesis and developmental processes, and expression of most of these genes were silenced in PBMCs. No changes in DNA methylation were found in genes displaying transiently induced changes in gene expression. In conclusion, aging-induced differential methylation often targets developmental genes and occurs mostly without change in gene expression.
Original languageEnglish
Article number9648
Pages (from-to)1523-1540
Number of pages18
JournalAge / the official journal of the American Aging Association
Volume36
Issue number3
DOIs
Publication statusPublished - 2014

Fingerprint

DNA Methylation
Blood Cells
Genome
Gene Expression
Methylation
Genes
Developmental Genes
Computational Biology
Epigenomics
Healthy Volunteers
Carcinogenesis
Biomarkers
Health

Keywords

  • activated receptor-alpha
  • human brain
  • transcriptional profile
  • caloric restriction
  • stem-cells
  • promoter
  • cancer
  • epigenetics
  • disease
  • tissue

Cite this

Steegenga, W.T. ; Boekschoten, M.V. ; Lute, C. ; Hooiveld, G.J.E.J. ; de Groot, P.J. ; Morris, T.J. ; Teschendorff, A.E. ; Butcher, L.M. ; Beck, S. ; Müller, M.R. / Genome-wide age-related changes in DNA methylation and gene expression in human PBMCs. In: Age / the official journal of the American Aging Association. 2014 ; Vol. 36, No. 3. pp. 1523-1540.
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abstract = "Aging is a progressive process that results in the accumulation of intra- and extracellular alterations that in turn contribute to a reduction in health. Age-related changes in DNA methylation have been reported before and may be responsible for aging-induced changes in gene expression, although a causal relationship has yet to be shown. Using genome-wide assays, we analyzed age-induced changes in DNA methylation and their effect on gene expression with and without transient induction with the synthetic transcription modulating agent WY14,643. To demonstrate feasibility of the approach, we isolated peripheral blood mononucleated cells (PBMCs) from five young and five old healthy male volunteers and cultured them with or without WY14,643. Infinium 450K BeadChip and Affymetrix Human Gene 1.1 ST expression array analysis revealed significant differential methylation of at least 5 {\%} (¿YO¿>¿5 {\%}) at 10,625 CpG sites between young and old subjects, but only a subset of the associated genes were also differentially expressed. Age-related differential methylation of previously reported epigenetic biomarkers of aging including ELOVL2, FHL2, PENK, and KLF14 was confirmed in our study, but these genes did not display an age-related change in gene expression in PBMCs. Bioinformatic analysis revealed that differentially methylated genes that lack an age-related expression change predominantly represent genes involved in carcinogenesis and developmental processes, and expression of most of these genes were silenced in PBMCs. No changes in DNA methylation were found in genes displaying transiently induced changes in gene expression. In conclusion, aging-induced differential methylation often targets developmental genes and occurs mostly without change in gene expression.",
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Genome-wide age-related changes in DNA methylation and gene expression in human PBMCs. / Steegenga, W.T.; Boekschoten, M.V.; Lute, C.; Hooiveld, G.J.E.J.; de Groot, P.J.; Morris, T.J.; Teschendorff, A.E.; Butcher, L.M.; Beck, S.; Müller, M.R.

In: Age / the official journal of the American Aging Association, Vol. 36, No. 3, 9648, 2014, p. 1523-1540.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Genome-wide age-related changes in DNA methylation and gene expression in human PBMCs

AU - Steegenga, W.T.

AU - Boekschoten, M.V.

AU - Lute, C.

AU - Hooiveld, G.J.E.J.

AU - de Groot, P.J.

AU - Morris, T.J.

AU - Teschendorff, A.E.

AU - Butcher, L.M.

AU - Beck, S.

AU - Müller, M.R.

PY - 2014

Y1 - 2014

N2 - Aging is a progressive process that results in the accumulation of intra- and extracellular alterations that in turn contribute to a reduction in health. Age-related changes in DNA methylation have been reported before and may be responsible for aging-induced changes in gene expression, although a causal relationship has yet to be shown. Using genome-wide assays, we analyzed age-induced changes in DNA methylation and their effect on gene expression with and without transient induction with the synthetic transcription modulating agent WY14,643. To demonstrate feasibility of the approach, we isolated peripheral blood mononucleated cells (PBMCs) from five young and five old healthy male volunteers and cultured them with or without WY14,643. Infinium 450K BeadChip and Affymetrix Human Gene 1.1 ST expression array analysis revealed significant differential methylation of at least 5 % (¿YO¿>¿5 %) at 10,625 CpG sites between young and old subjects, but only a subset of the associated genes were also differentially expressed. Age-related differential methylation of previously reported epigenetic biomarkers of aging including ELOVL2, FHL2, PENK, and KLF14 was confirmed in our study, but these genes did not display an age-related change in gene expression in PBMCs. Bioinformatic analysis revealed that differentially methylated genes that lack an age-related expression change predominantly represent genes involved in carcinogenesis and developmental processes, and expression of most of these genes were silenced in PBMCs. No changes in DNA methylation were found in genes displaying transiently induced changes in gene expression. In conclusion, aging-induced differential methylation often targets developmental genes and occurs mostly without change in gene expression.

AB - Aging is a progressive process that results in the accumulation of intra- and extracellular alterations that in turn contribute to a reduction in health. Age-related changes in DNA methylation have been reported before and may be responsible for aging-induced changes in gene expression, although a causal relationship has yet to be shown. Using genome-wide assays, we analyzed age-induced changes in DNA methylation and their effect on gene expression with and without transient induction with the synthetic transcription modulating agent WY14,643. To demonstrate feasibility of the approach, we isolated peripheral blood mononucleated cells (PBMCs) from five young and five old healthy male volunteers and cultured them with or without WY14,643. Infinium 450K BeadChip and Affymetrix Human Gene 1.1 ST expression array analysis revealed significant differential methylation of at least 5 % (¿YO¿>¿5 %) at 10,625 CpG sites between young and old subjects, but only a subset of the associated genes were also differentially expressed. Age-related differential methylation of previously reported epigenetic biomarkers of aging including ELOVL2, FHL2, PENK, and KLF14 was confirmed in our study, but these genes did not display an age-related change in gene expression in PBMCs. Bioinformatic analysis revealed that differentially methylated genes that lack an age-related expression change predominantly represent genes involved in carcinogenesis and developmental processes, and expression of most of these genes were silenced in PBMCs. No changes in DNA methylation were found in genes displaying transiently induced changes in gene expression. In conclusion, aging-induced differential methylation often targets developmental genes and occurs mostly without change in gene expression.

KW - activated receptor-alpha

KW - human brain

KW - transcriptional profile

KW - caloric restriction

KW - stem-cells

KW - promoter

KW - cancer

KW - epigenetics

KW - disease

KW - tissue

U2 - 10.1007/s11357-014-9648-x

DO - 10.1007/s11357-014-9648-x

M3 - Article

VL - 36

SP - 1523

EP - 1540

JO - Age / the official journal of the American Aging Association

JF - Age / the official journal of the American Aging Association

SN - 0161-9152

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M1 - 9648

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