title: Pubertal development in healthy children is mirrored by DNA methylation patterns in peripheral blood.
abstract: Puberty marks numerous physiological processes which are initiated by central activation of the hypothalamic-pituitary-gonadal axis, followed by development of secondary sexual characteristics. To a large extent, pubertal timing is heritable, but current knowledge of genetic polymorphisms only explains few months in the large inter-individual variation in the timing of puberty. We have analysed longitudinal genome-wide changes in DNA methylation in peripheral blood samples (n = 102) obtained from 51 healthy children before and after pubertal onset. We show that changes in single methylation sites are tightly associated with physiological pubertal transition and altered reproductive hormone levels. These methylation sites cluster in and around genes enriched for biological functions related to pubertal development. Importantly, we identified that methylation of the genomic region containing the promoter of TRIP6 was co-ordinately regulated as a function of pubertal development. In accordance, immunohistochemistry identified TRIP6 in adult, but not pre-pubertal, testicular Leydig cells and circulating TRIP6 levels doubled during puberty. Using elastic net prediction models, methylation patterns predicted pubertal development more accurately than chronological age. We demonstrate for the first time that pubertal attainment of secondary sexual characteristics is mirrored by changes in DNA methylation patterns in peripheral blood. Thus, modulations of the epigenome seem involved in regulation of the individual pubertal timing.
authors.affiliation: Department of Growth and Reproduction, Section GR-5064, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.|International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC)Copenhagen, Denmark.
authors.forename: Kristian
authors.initials: K
authors.lastname: Almstrup
authors.affiliation: Department of Growth and Reproduction, Section GR-5064, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.|International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC)Copenhagen, Denmark.
authors.forename: Marie
authors.initials: M
authors.lastname: Lindhardt Johansen
authors.affiliation: Department of Growth and Reproduction, Section GR-5064, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.|International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC)Copenhagen, Denmark.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Busch
authors.affiliation: Department of Growth and Reproduction, Section GR-5064, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.|International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC)Copenhagen, Denmark.
authors.forename: Casper P
authors.initials: CP
authors.lastname: Hagen
authors.affiliation: Department of Growth and Reproduction, Section GR-5064, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
authors.forename: John E
authors.initials: JE
authors.lastname: Nielsen
authors.affiliation: Department of Growth and Reproduction, Section GR-5064, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.|International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC)Copenhagen, Denmark.|Institute of Public Health, Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jørgen Holm
authors.initials: JH
authors.lastname: Petersen
authors.affiliation: Department of Growth and Reproduction, Section GR-5064, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.|International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC)Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Juul
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation / Q000502:physiology*; D005260:Female; D006801:Humans; D060588:LIM Domain Proteins / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D011401:Promoter Regions, Genetic / Q000502:physiology*; D011627:Puberty / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060588:LIM Domain Proteins; C000614140:TRIP6 protein, human; D014157:Transcription Factors