Methylome profiling of healthy and central precocious puberty girls

Danielle S. Bessa, Mariana Maschietto, Carlos Francisco Aylwin, Ana P.M. Canton, Vinicius N. Brito, Delanie B. Macedo, Marina Cunha-Silva, Heloísa M.C. Palhares, Elisabete A.M.R. de Resende, Maria de Fátima Borges, Berenice B. Mendonca, Irene Netchine, Ana C.V. Krepischi, Alejandro Lomniczi, Sergio Ojeda, Ana Claudia Latronico

    Research output: Contribution to journalArticle

    1 Citation (Scopus)

    Abstract

    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.

    Original languageEnglish (US)
    Number of pages1
    JournalClinical Epigenetics
    Volume10
    Issue number1
    DOIs
    StatePublished - Nov 22 2018

    Fingerprint

    Puberty
    Zinc Fingers
    DNA Methylation
    Genes
    Methylation
    Genomic Imprinting
    Precocious Puberty
    DNA Fingerprinting
    X Chromosome
    Macaca mulatta
    Genetic Promoter Regions
    Epigenomics
    Hypothalamus
    Central Precocious Puberty
    Leukocytes
    Genome
    DNA

    Keywords

    • Central precocious puberty
    • DNA methylation
    • Epigenetics
    • Genomic imprinting
    • Human puberty
    • Zinc finger genes

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Developmental Biology
    • Genetics(clinical)

    Cite this

    Bessa, D. S., Maschietto, M., Aylwin, C. F., Canton, A. P. M., Brito, V. N., Macedo, D. B., ... Latronico, A. C. (2018). Methylome profiling of healthy and central precocious puberty girls. Clinical Epigenetics, 10(1). https://doi.org/10.1186/s13148-018-0581-1

    Methylome profiling of healthy and central precocious puberty girls. / Bessa, Danielle S.; Maschietto, Mariana; Aylwin, Carlos Francisco; Canton, Ana P.M.; Brito, Vinicius N.; Macedo, Delanie B.; Cunha-Silva, Marina; Palhares, Heloísa M.C.; de Resende, Elisabete A.M.R.; Borges, Maria de Fátima; Mendonca, Berenice B.; Netchine, Irene; Krepischi, Ana C.V.; Lomniczi, Alejandro; Ojeda, Sergio; Latronico, Ana Claudia.

    In: Clinical Epigenetics, Vol. 10, No. 1, 22.11.2018.

    Research output: Contribution to journalArticle

    Bessa, DS, Maschietto, M, Aylwin, CF, Canton, APM, Brito, VN, Macedo, DB, Cunha-Silva, M, Palhares, HMC, de Resende, EAMR, Borges, MDF, Mendonca, BB, Netchine, I, Krepischi, ACV, Lomniczi, A, Ojeda, S & Latronico, AC 2018, 'Methylome profiling of healthy and central precocious puberty girls', Clinical Epigenetics, vol. 10, no. 1. https://doi.org/10.1186/s13148-018-0581-1
    Bessa DS, Maschietto M, Aylwin CF, Canton APM, Brito VN, Macedo DB et al. Methylome profiling of healthy and central precocious puberty girls. Clinical Epigenetics. 2018 Nov 22;10(1). https://doi.org/10.1186/s13148-018-0581-1
    Bessa, Danielle S. ; Maschietto, Mariana ; Aylwin, Carlos Francisco ; Canton, Ana P.M. ; Brito, Vinicius N. ; Macedo, Delanie B. ; Cunha-Silva, Marina ; Palhares, Heloísa M.C. ; de Resende, Elisabete A.M.R. ; Borges, Maria de Fátima ; Mendonca, Berenice B. ; Netchine, Irene ; Krepischi, Ana C.V. ; Lomniczi, Alejandro ; Ojeda, Sergio ; Latronico, Ana Claudia. / Methylome profiling of healthy and central precocious puberty girls. In: Clinical Epigenetics. 2018 ; Vol. 10, No. 1.
    @article{843c880786bb421186545f71b8529bab,
    title = "Methylome profiling of healthy and central precocious puberty girls",
    abstract = "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.",
    keywords = "Central precocious puberty, DNA methylation, Epigenetics, Genomic imprinting, Human puberty, Zinc finger genes",
    author = "Bessa, {Danielle S.} and Mariana Maschietto and Aylwin, {Carlos Francisco} and Canton, {Ana P.M.} and Brito, {Vinicius N.} and Macedo, {Delanie B.} and Marina Cunha-Silva and Palhares, {Helo{\'i}sa M.C.} and {de Resende}, {Elisabete A.M.R.} and Borges, {Maria de F{\'a}tima} and Mendonca, {Berenice B.} and Irene Netchine and Krepischi, {Ana C.V.} and Alejandro Lomniczi and Sergio Ojeda and Latronico, {Ana Claudia}",
    year = "2018",
    month = "11",
    day = "22",
    doi = "10.1186/s13148-018-0581-1",
    language = "English (US)",
    volume = "10",
    journal = "Clinical Epigenetics",
    issn = "1868-7075",
    publisher = "Springer Verlag",
    number = "1",

    }

    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

    AU - Latronico, Ana Claudia

    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

    UR - http://www.scopus.com/inward/record.url?scp=85057093756&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=85057093756&partnerID=8YFLogxK

    U2 - 10.1186/s13148-018-0581-1

    DO - 10.1186/s13148-018-0581-1

    M3 - Article

    C2 - 30466473

    AN - SCOPUS:85057093756

    VL - 10

    JO - Clinical Epigenetics

    JF - Clinical Epigenetics

    SN - 1868-7075

    IS - 1

    ER -