Methylome profiling of healthy and central precocious puberty girls

Author(s):Show less -

Bessa, Danielle S. ^[1] ; Maschietto, Mariana ^[2] ; Aylwin, Carlos Francisco ^[3] ; Canton, Ana P. M. ^{[4, 1]} ; Brito, Vinicius N. ^[1] ; Macedo, Delanie B. ^[1] ; Cunha-Silva, Marina ^[1] ; Palhares, Heloisa M. C. ^[5] ; de Resende, Elisabete A. M. R. ^[5] ; Borges, Maria de Fatima ^[5] ; Mendonca, Berenice B. ^[1] ; Netchine, Irene ^[4] ; Krepischi, Ana C. V. ^[6] ; Lomniczi, Alejandro ^{[3, 7]} ; Ojeda, Sergio R. ^[7] ; Latronico, Ana Claudia ^{[1, 8]}

Affiliation

^[1] Univ Sao Paulo, Sao Paulo Med Sch, Clin Hosp, Lab Hormones & Mol Genet, Div Endocrinol & Metab, Dev Endocrinol Unit, LIM42, Sao Paulo, SP - Brazil

^[2] Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Biosci Natl Lab LNBio, Campinas, SP - Brazil

^[3] OHSU, Oregon Natl Primate Res Ctr, Div Genet, Beaverton, OR - USA

^[4] Sorbonne Univ, Hop Armand Trousseau, AP HP, Ctr Rech St Antoine, UMR S 938, INSERM, Explorat Fonct Endocriniennes, Paris - France

^[5] Triangulo Mineiro Fed Univ, Div Endocrinol, Uberaba, MG - Brazil

^[6] Univ Sao Paulo, Inst Biosci, Dept Genet & Evolutionary Biol, Sao Paulo, SP - Brazil

^[7] OHSU, Div Neurosci, Oregon Natl Primate Res Ctr, Beaverton, OR - USA

^[8] Univ Sao Paulo, Hosp Clin, Fac Med, Dept Clin Med, Disciplina Endocrinol & Metab, Av Dr Eneas de Carvalho Aguiar 255, 7 Andar, BR-05403900 Sao Paulo - Brazil

• Document type: Journal article
• Source: CLINICAL EPIGENETICS; v. 10, NOV 22 2018.
• Web of Science Citations: 0

Abstract

BackgroundRecent studies demonstrated that changes in DNA methylation (DNAm) and inactivation of two imprinted genes (MKRN3 and DLK1) alter the onset of female puberty. We aimed to investigate the association of DNAm profiling with the timing of human puberty analyzing the genome-wide DNAm patterns of peripheral blood leukocytes from ten female patients with central precocious puberty (CPP) and 33 healthy girls (15 pre- and 18 post-pubertal). For this purpose, we performed comparisons between the groups: pre- versus post-pubertal, CPP versus pre-pubertal, and CPP versus post-pubertal.ResultsAnalyzing the methylome changes associated with normal puberty, we identified 120 differentially methylated regions (DMRs) when comparing pre- and post-pubertal healthy girls. Most of these DMRs were hypermethylated in the pubertal group (99%) and located on the X chromosome (74%). Only one genomic region, containing the promoter of ZFP57, was hypomethylated in the pubertal group. ZFP57 is a transcriptional repressor required for both methylation and imprinting of multiple genomic loci. ZFP57 expression in the hypothalamus of female rhesus monkeys increased during peripubertal development, suggesting enhanced repression of downstream ZFP57 target genes. Fourteen other zinc finger (ZNF) genes were related to the hypermethylated DMRs at normal puberty. Analyzing the methylome changes associated with CPP, we demonstrated that the patients with CPP exhibited more hypermethylated CpG sites compared to both pre-pubertal (81%) and pubertal (89%) controls. Forty-eight ZNF genes were identified as having hypermethylated CpG sites in CPP.ConclusionMethylome profiling of girls at normal and precocious puberty revealed a widespread pattern of DNA hypermethylation, indicating that the pubertal process in humans is associated with specific changes in epigenetically driven regulatory control. Moreover, changes in methylation of several ZNF genes appear to be a distinct epigenetic modification underlying the initiation of human puberty. (AU)

• FAPESP's process: 13/03236-5 - New approaches and methodologies in molecular-genetic studies of growth and pubertal development disorders
• Grantee: Alexander Augusto de Lima Jorge
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 15/06281-7 - Characterization of the epigenetic regulation in human solid paediatric tumours
• Grantee: Mariana Camargo Maschietto
• Support type: Scholarships in Brazil - Young Researchers