Mining Novel Candidate Imprinted Genes Using Genome-Wide Methylation Screening and Literature Review

Abstract

Large-scale transcriptome and methylome data analyses obtained by high-throughput technologies have been enabling the identification of novel imprinted genes. We investigated genome-wide DNA methylation patterns in multiple human tissues, using a high-resolution microarray to uncover hemimethylated CpGs located in promoters overlapping CpG islands, aiming to identify novel candidate imprinted genes. Using our approach, we recovered~30% of the known human imprinted genes, and a further 168 candidates were identified, 61 of which with at least three hemimethylated CpGs shared by more than two tissue types. Thirty-four of these candidate genes are members of the protocadherin cluster on 5q31.3; in mice, protocadherin genes have non-imprinted random monoallelic expression, which might also be the case in humans. Among the remaining 27 genes, ZNF331 was recently validated as an imprinted gene, and six of them have been reported as candidates, supporting our prediction. Five candidates (CCDC166, ARC, PLEC, TONSL, and VPS28) map to 8q24.3, and might constitute a novel imprinted cluster. Additionally, we performed a comprehensive compilation of known human and mice imprinted genes from literature and databases, and a comparison among high-throughput imprinting studies in humans. The screening for hemimethylated CpGs shared by multiple human tissues, together with the extensive review, appears to be a useful approach to reveal candidate imprinted genes.

First genome-wide CNV mapping in FELIS CATUS using next generation sequencing data

“…This gene has been previously found in a rare CNV in humans [ 54 ] where the CNV homozygous deletion was not associated to an abnormal phenotype. More recently, [ 55 ] have found this gene as associated with diabetes in humans and [ 56 ] have classified the gene as a potential imprinted gene. The PTCHD3 gene is not yet included in the Imprinted Genes database ( www.geneimprint.com ), as no other gene found in the CNVRs here reported.…”

Increased copy number of imprinted genes in the chromosomal region 20q11-q13.32 is associated with resistance to antitumor agents in cancer cell lines

“…Chromosomal location of the imprinted genes was identified according to the information in the Catalog of Imprinted Genes [47][48][49], Bonaldi et al [52], and biomedical literature. For those imprinted genes that had minor discrepancies among their reported chromosomal location from different sources, their chromosomal location was reported according to GeneCards [76,77].…”

“…S3 shows the combined distribution of gene-averaged methylation beta values among 515 imprinted gene regions and separate distribution plots for each imprinted gene region category in 645 cell lines from all cancer categories combined. Among the 6 gene regions, the imprinted status, corresponding to a distribution peak around methylation beta values of 0.5, which would be characteristic of hemimethylated regions that would potentially represent imprinted sites [52,[107][108][109], was observed for the TSS200 and 5′ UTR gene regions located upstream of imprinted genes, and the first exons of imprinted genes. This location of hemimethylated gene regions is consistent with the previously established overlap between differentially methylated regions (DMR) and promoter regions of imprinted genes [110].…”

“…We also thank Dr. Larry Rubinstein (Biometric Research Program, NCI) for assistance with administrative coordination of the project work and Dr. Melanie Simpson (Frederick National Laboratory for Cancer Research) for technical recommendations. We thank Dr. Ana Krepischi (Institute of Biosciences, University of São Paulo, Brazil) for the communication about the availability of imprinted gene data from a previously published dataset [52]. The views expressed in this article are the personal opinions of the authors and do not necessarily reflect policy of the US National Cancer Institute.…”