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

• Published in: Frontiers in genetics Vol. 9; p. 36
• Main Authors: de Sá Machado Araújo, Graziela, da Silva Francisco Junior, Ronaldo, dos Santos Ferreira, Cristina, Mozer Rodrigues, Pedro Thyago, Terra Machado, Douglas, Louvain de Souza, Thais, Teixeira de Souza, Jozimara, Figueiredo Osorio da Silva, Cleiton, Alves da Silva, Antônio Francisco, Andrade, Claudia Caixeta Franco, da Silva, Alan Tardin, Ramos, Victor, Garcia, Ana Beatriz, Machado, Filipe Brum, Medina-Acosta, Enrique
• Format: Journal Article
• Language: English
• Published: Frontiers Media S.A 01-03-2018
• Subjects: GCSAML; Genetics; GRB10; LOC284240; OR2L13; PARD6G-AS1; ZNF124
• ISSN: 1664-8021; 1664-8021
• DOI: 10.3389/fgene.2018.00036

A hallmark of imprinted genes in mammals is the occurrence of parent-of-origin-dependent asymmetry of DNA cytosine methylation (5
m
C) of alleles at CpG islands (CGIs) in their promoter regions. This 5
m
CpG asymmetry between the parental alleles creates allele-specific imprinted differentially methylated regions (iDMRs). iDMRs are often 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 to 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 candidate iDMRs display gametic 5
m
CpG asymmetry, and another 96 are candidate secondary iDMRs. We established the maternal origin of the 5
m
CpG imprints of one gametic (
PARD6G-AS1
) and one secondary (
GCSAML
) iDMRs. We also found a constitutively hemimethylated, nonimprinted domain at the
PWWP2AP1
promoter CGI with oocyte-derived methylation asymmetry. Given that the 5
m
CpG level at the iDMRs is not a sufficient criterion to predict active or silent locus states and that iDMRs can regulate genes from a distance of more than 1 Mb, we used RNA-Seq experiments from the Genotype-Tissue Expression project and public archives to assess the transcriptional expression profiles of SNPs across 4.6 Mb spans around the novel maternal iDMRs. 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 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 5
m
CpG imprints are perturbed in several hematopoietic cancers. We conclude that the maternal 5
m
CpG imprints at
PARD6G-AS1
and
GCSAML
iDMRs are decoupled from parent-of-origin transcriptional expression effects in multiple tissues.