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Front. Genet. | doi: 10.3389/fgene.2018.00036

Maternal 5mCpG Imprints at the PARD6G-AS1 and GCSAML Differentially Methylated Regions are Decoupled from Parent-of-Origin Expression Effects in Multiple Human Tissues

  • 1Center for Biosciences and Biotechnology, State University of Norte Fluminense, Brazil
  • 2Laboratório Nacional de Computação Científica (LNCC), Brazil
  • 3Faculdade de Medicina de Campos, Brazil
  • 4Secretaria de Estado da Saúde do Espírito Santo, Brazil
  • 5Faculdade Metropolitana São Carlos, Brazil
  • 6Ribeirão Preto Medical School, University of São Paulo, Brazil

A hallmark of imprinted genes in mammals is the occurrence of parent-of-origin-dependent asymmetry of DNA cytosine methylation (5mC) of alleles at CpG islands (CGIs) in their promoter regions. The 5mCpG asymmetry between the parental alleles creates allele-specific imprinted differentially methylated regions (iDMRs). iDMRs often are coupled to the transcriptional repression of the methylated allele and the activation of the unmethylated allele in a tissue-specific, developmental-stage-specific and/or isoform-specific fashion. iDMRs function as regulatory platforms, built through the recruitment of chemical modifications on histones to achieve differential, parent-of-origin-dependent chromatin segmentation states. Here, we used a comparative computational data mining approach to identify 125 novel constitutive candidate iDMRs that integrate the maximal number of allele-specific methylation region records overlapping CGIs in human methylomes. Twenty-nine new candidate iDMRs display gametic 5mCpG asymmetry, and another 96 are candidate secondary iDMRs. We established the maternal origin of the 5mCpG imprints of one gametic (PARD6G-AS1) and one secondary (GCSAML) iDMRs. We also found a constitutive hemimethylated, nonimprinted domain at the PWWP2AP1 promotor CGI with oocyte-derived methylation asymmetry. Given that the 5mCpG level at the iDMRs is not a sufficient criterion to predict active or silent locus states and that iDMRs can regulate genes over a distance of 1-Mb, we assessed the allele transcriptional expression profiles in SNPs across 4.6-Mb spans around the novel maternal iDMRs in RNA-Seq experiments from the Genotype-Tissue Expression project and public archives. We showed that PARD6G-AS1 and GCSAML are expressed biallelically in multiple tissues. We found evidence of tissue-specific monoallelic expression of ZNF124 and OR2L13, located 363-kb upstream and 419-kb downstream, respectively, of the GCSAML iDMR. We hypothesize that the GCSAML iDMR regulates the tissue-specific, monoallelic expression of ZNF124 but not of OR2L13. We also annotated the non-coding epigenomic marks in the two maternal iDMRs using data from the Roadmap Epigenomics project and showed that the PARD6G-AS1 and GCSAML iDMRs achieve contrasting activation and repression chromatin segmentations. Lastly, we found that the maternal 5mCpG imprints are perturbed in several hematopoietic cancers. We conclude that the maternal 5mCpG imprints at PARD6G-AS1 and GCSAML iDMRs are decoupled from parent-of-origin transcriptional expression effects in multiple tissues.

Keywords: PARD6G-AS1, GCSAML, WRB, ZNF124, OR2L13, LOC284240, Genomic Imprinting, chromatin segmentation, allele-specific expression, ZDBF2, Grb10, Imprinting disease

Received: 28 Sep 2017; Accepted: 29 Jan 2018.

Edited by:

Rui Henrique, IPO Porto, Portugal

Reviewed by:

Ian C. Weaver, Dalhousie University, Canada
Antonius Plagge, University of Liverpool, United Kingdom  

Copyright: © 2018 Machado Araújo, da Silva Francisco Junior, Ferreira, Rodrigues, Machado, Louvain De Souza, De Souza, Osório, Da Silva, Andrade, Da Silva, Ramos, Garcia, Machado and Medina-Acosta. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Enrique Medina-Acosta, State University of Norte Fluminense, Center for Biosciences and Biotechnology, Avenida Alberto Lamego 2000, CBB/LBT, Campos dos Goytacazes, 28013602, Rio de Janeiro, Brazil,