TY - JOUR
T1 - Methylome profiling of healthy and central precocious puberty girls
AU - Bessa, Danielle S.
AU - Maschietto, Mariana
AU - Aylwin, Carlos Francisco
AU - Canton, Ana P.M.
AU - Brito, Vinicius N.
AU - Macedo, Delanie B.
AU - Cunha-Silva, Marina
AU - Palhares, Heloísa M.C.
AU - de Resende, Elisabete A.M.R.
AU - Borges, Maria de Fátima
AU - Mendonca, Berenice B.
AU - Netchine, Irene
AU - Krepischi, Ana C.V.
AU - Lomniczi, Alejandro
AU - Ojeda, Sergio R.
AU - Latronico, Ana Claudia
N1 - Funding Information:
This work was supported by grants from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (to DSB); Fundação de Amparo à Pesquisa do Estado de São Paulo 2015/06281-7 (to MM), and 2013/03236-5 (to ACL); Conselho Nacional de Desenvolvimento Científico e Tecnológico 302849/2015-7 (to ACL); and National Institute of Health 1R01HD084542 and 8P51OD011092 for the operation of the Oregon National Primate Research Center (to SRO and AL).
PY - 2018/11/22
Y1 - 2018/11/22
N2 - BACKGROUND: Recent 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. RESULTS: Analyzing 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. CONCLUSION: Methylome 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.
AB - BACKGROUND: Recent 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. RESULTS: Analyzing 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. CONCLUSION: Methylome 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.
KW - Central precocious puberty
KW - DNA methylation
KW - Epigenetics
KW - Genomic imprinting
KW - Human puberty
KW - Zinc finger genes
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U2 - 10.1186/s13148-018-0581-1
DO - 10.1186/s13148-018-0581-1
M3 - Article
C2 - 30466473
AN - SCOPUS:85057093756
SN - 1868-7075
VL - 10
SP - 146
JO - Clinical epigenetics
JF - Clinical epigenetics
IS - 1
ER -