Analysis of epigenetic changes in survivors of preterm birth reveals the effect of gestational age and evidence for a long term legacy

被引:84
作者
Cruickshank, Mark N. [1 ,2 ]
Oshlack, Alicia [2 ,3 ]
Theda, Christiane [1 ,4 ,5 ]
Davis, Peter G. [2 ,4 ,5 ]
Martino, David [6 ]
Sheehan, Penelope [5 ]
Dai, Yun [1 ]
Saffery, Richard [2 ,6 ]
Doyle, Lex W. [2 ,4 ,5 ]
Craig, Jeffrey M. [1 ,2 ]
机构
[1] Royal Childrens Hosp, MCRI, Early Life Epigenet Grp, Parkville, Vic 3052, Australia
[2] Univ Melbourne, Royal Childrens Hosp, Dept Paediat, Parkville, Vic 3052, Australia
[3] Royal Childrens Hosp, MCRI, Bioinformat Grp, Parkville, Vic 3052, Australia
[4] Royal Womens Hosp, Neonatal Serv, Parkville, Vic 3052, Australia
[5] Univ Melbourne, Dept Obstet & Gynaecol, Royal Womens Hosp, Parkville, Vic 3052, Australia
[6] Royal Childrens Hosp, MCRI, Canc & Dev Epigenet Grp, Parkville, Vic 3052, Australia
来源
GENOME MEDICINE | 2013年 / 5卷
基金
英国医学研究理事会;
关键词
HEMATOPOIETIC STEM-CELLS; DNA METHYLATION; GENE-EXPRESSION; INNATE IMMUNITY; BLOOD SPOTS; EARLY-LIFE; MICROARRAY; ARRAY; MECHANISM; NLRC5;
D O I
10.1186/gm500
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Background: Preterm birth confers a high risk of adverse long term health outcomes for survivors, yet the underlying molecular mechanisms are unclear. We hypothesized that effects of preterm birth can be mediated through measurable epigenomic changes throughout development. We therefore used a longitudinal birth cohort to measure the epigenetic mark of DNA methylation at birth and 18 years comparing survivors of extremely preterm birth with infants born at term. Methods: Using 12 extreme preterm birth cases and 12 matched, term controls, we extracted DNA from archived neonatal blood spots and blood collected in a similar way at 18 years of age. DNA methylation was measured at 347,789 autosomal locations throughout the genome using Infinium HM450 arrays. Representative methylation differences were confirmed by Sequenom MassArray EpiTYPER. Results: At birth we found 1,555 sites with significant differences in methylation between term and preterm babies. At 18 years of age, these differences had largely resolved, suggesting that DNA methylation differences at birth are mainly driven by factors relating to gestational age, such as cell composition and/or maturity. Using matched longitudinal samples, we found evidence for an epigenetic legacy associated with preterm birth, identifying persistent methylation differences at ten genomic loci. Longitudinal comparisons of DNA methylation at birth and 18 years uncovered a significant overlap between sites that were differentially-methylated at birth and those that changed with age. However, we note that overlapping sites may either differ in the same (300/1,555) or opposite (431/1,555) direction during gestation and aging respectively. Conclusions: We present evidence for widespread methylation differences between extreme preterm and term infants at birth that are largely resolved by 18 years of age. These results are consistent with methylation changes associated with blood cell development, cellular composition, immune induction and age at these time points. Finally, we identified ten probes significantly associated with preterm individuals and with greater than 5% methylation discordance at birth and 18 years that may reflect a long term epigenetic legacy of preterm birth.
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页数:12
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共 88 条
  • [1] Meta-Analysis of Neurobehavioral Outcomes in Very Preterm and/or Very Low Birth Weight Children
    Aarnoudse-Moens, Cornelieke Sandrine Hanan
    Weisglas-Kuperus, Nynke
    van Goudoever, Johannes Bernard
    Oosterlaan, Jaap
    [J]. PEDIATRICS, 2009, 124 (02) : 717 - 728
  • [2] High quality methylome-wide investigations through next-generation sequencing of DNA from a single archived dry blood spot
    Aberg, Karolina A.
    Xie, Lin Y.
    Nerella, Srilaxmi
    Copeland, William E.
    Costello, E. Jane
    van den Oord, Edwin J. C. G.
    [J]. EPIGENETICS, 2013, 8 (05) : 542 - 547
  • [3] Neonatal adaptive immunity comes of age
    Adkins, B
    Leclerc, C
    Marshall-Clarke, S
    [J]. NATURE REVIEWS IMMUNOLOGY, 2004, 4 (07) : 553 - 564
  • [4] Selective Inner Hair Cell Loss in Prematurity: A Temporal Bone Study of Infants from a Neonatal Intensive Care Unit
    Amatuzzi, Monica
    Liberman, M. Charles
    Northrop, Clarinda
    [J]. JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY, 2011, 12 (05): : 595 - 604
  • [5] [Anonymous], 2012, MINFI ANAL ILLUMINAS
  • [6] Methodological issues in outcome studies of at-risk infants
    Aylward, GP
    [J]. JOURNAL OF PEDIATRIC PSYCHOLOGY, 2002, 27 (01) : 37 - 45
  • [7] Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion
    Beerman, Isabel
    Bhattacharya, Deepta
    Zandi, Sasan
    Sigvardsson, Mikael
    Weissman, Irving L.
    Bryder, David
    Rossi, Derrick J.
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (12) : 5465 - 5470
  • [8] Behrman RE., 2007, Preterm birth: causes, consequences, and prevention, DOI [10.17226/11622, DOI 10.17226/11622]
  • [9] CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING
    BENJAMINI, Y
    HOCHBERG, Y
    [J]. JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) : 289 - 300
  • [10] Guthrie card methylomics identifies temporally stable epialleles that are present at birth in humans
    Beyan, Huriya
    Down, Thomas A.
    Ramagopalan, Sreeram V.
    Uvebrant, Kristina
    Nilsson, Anita
    Holland, Michelle L.
    Gemma, Carolina
    Giovannoni, Gavin
    Boehm, Bernhard O.
    Ebers, George C.
    Lernmark, Ake
    Cilio, Corrado M.
    Leslie, R. David
    Rakyan, Vardhman K.
    [J]. GENOME RESEARCH, 2012, 22 (11) : 2138 - 2145