SNP-guided identification of monoallelic DNA-methylation events from enrichment-based sequencing data

Steyaert, Sandra; Criekinge, Wim Van; Paepe, Annick De; Denil, Simon; Mensaert, Klaas; Vandepitte, Katrien; Berghe, Wim Vanden; Trooskens, Geert; Meyer, Tim De

doi:10.1101/002352

Cited by 3 publications

(10 citation statements)

References 52 publications

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“…However, the downside of this methodology is that non-imprinted genes may also show monoallelic expression [1,26], and imprinted expression is mostly tissue-specific [20,27]. Another approach that has been extensively explored is the search for epigenetic signature of imprinted regions, using methylation microarrays or next generation sequencing [11][12][13]15,16,18]. Although methylation array does not provide data of allelic methylation, the advantage of this approach is that, in most tissues, DNA methylation of IGs is preserved throughout development and adult life, irrespective of their expression status [3,24].…”

Section: Discussionmentioning

confidence: 99%

“…We compared the high-throughput imprinting studies in human reported since 2011 (Table S3) [11][12][13][14][15][16][17][18][19][20]. Different methods were designed to screen novel candidate IGs.…”

Section: Discussionmentioning

confidence: 99%

“…Only one gene (DLX5) has a contradictory imprinting status in humans between both databases; given that this gene is not imprinted in mouse, its imprinting status needs to be better characterized in human. A growing number of putative IGs, in which allele-specific expression (ASE) has been demonstrated in one or more human tissues, have been described in the past few years using genome-wide methodologies-ARMC3, WDR27, WRB, NHP2L1, AGBL3, MCCC1, MIR512-1, MX2, NOTCH3, NDUFB, FAM19A5, RMI2, HERC3, SORCS2, ANTXR1, PTPRN2, PMF1, PRSS50, THEGL, UGT2B4, FRG1, DHFR, KIF25, NAPRT1, INTS4, AMPD3, LPAR6, MEG9, RP11-7F17.7, SNHG14, GNG7, and CST1 [11,[15][16][17][18][19][20] (all known and candidate IGs are listed and compared in Table S3). ASE in some tissues and/or differential methylation patterns are indicative of imprinting, but, for validating candidate IGs, the analysis of ASE in family trios is necessary to exclude random monoallelic expression and to distinguish the candidates from possible cis-regulatory elements [23].…”

Section: Compilation Of Known Imprinted Genes In Human and Micementioning

confidence: 99%

“…In general, the approaches used to identify novel IGs are based on three main features: presence of an epigenetic signature, monoallelic expression dependent on parental origin, and specific characteristics of the DNA sequence (such as Short interspersed nuclear elements-SINE-exclusion) [3]. Currently, large-scale transcriptome and methylome analyses of data obtained by high-throughput technologies, such as microarrays and next-generation sequencing, are enabling the identification of new candidate IGs [11][12][13][14][15][16][17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Compilation Of Known Imprinted Genes In Human and Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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“…Contrasting previous genome-wide methods, no DNA genotyping data is required, as we solely rely on genotyping of RNA-seq data. The basic rationale is that in case of 100% imprinting, no heterozygous samples can be found in RNA-seq data, as they perfectly resemble homozygous samples (only a single allele is expressed) (see Methods section and Steyaert et al 27 ). The established imprinting model describes the data for each SNP as a mixture of homozygous and heterozygous samples, more specifically as a mixture of genotype dependent binomial distributions, with weights derived from Hardy-Weinberg equilibrium.…”

Section: Detection Of Imprinting In Healthy Breast Tissuementioning

confidence: 99%

A Comprehensive Overview of Genomic Imprinting in Breast & Its Deregulation in Cancer

Goovaerts

Steyaert

Vandenbussche

et al. 2018

Preprint

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Genomic imprinting, the parent-of-origin specific monoallelic expression of genes, plays an important role in growth and development. Loss of imprinting of individual genes has been found in varying cancers, yet data-analytical challenges have impeded systematic studies so far. We developed a mixture distribution model to detect monoallelically expressed loci in a genome-wide manner without the need for genotyping data, and applied the methodology on TCGA breast tissue RNA-seq data. We identified 35 putatively imprinted genes in healthy breast. In breast cancer however, HM13 was featured by significant loss of imprinting and expression upregulation, which could be linked to DNA demethylation. Other imprinted genes (25 out of 35) demonstrated consistent expression downregulation in breast cancer, which often correlated with loss of imprinting. A breast imprinted gene network, deregulated in cancer, might hence be present. In summary, our novel methodology highlights the massive deregulation of imprinting in breast cancer.

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Alterations of monoallelic DNA methylation in breast cancer

А.С.¹,

Калинкин²,

Немцова³

et al. 2021

Nauchno-Prakticheskii Zhurnal «Medicinskaia Genetika

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Цель. Изучение изменений в образцах злокачественных опухолей молочной железы статуса метилирования остатков цитозина в составе CpG-островков, моноаллельно метилированных в норме. Методы. Для определения CpG-динуклеотидов, моноаллельно метилированных в опухолевых и нормальных тканях молочной железы, использовали полученные авторами ранее результаты широкогеномного бисульфитного секвенирования Xmal-RRBS. Изменения моноаллельного метилирования в опухолях визуализировали с помощью гистограмм для различных метилотипов молочной железы. Результаты. В геномах умеренно метилированных опухолей нормально моноаллельно метилированные CpG-динуклеотиды имеют тенденцию к почти равновероятному изменению как в неметилированное, так и в полностью метилированное состояния. В геномах гиперметилированных опухолей нормально моноаллельно метилированные CpG-динуклеотиды чаще меняют своё состояние на полностью метилированное. Заключение. Наблюдаемый характер изменений позволяет предположить, что динамика диктуется в умеренно метилированных опухолях процессами, не определяющими её вектор, а в гиперметилированных - дополнительно - направленным процессом, повышающим уровень метилирования CpG-динуклеотидов. По аналогии с ранее опубликованными результатами исследования динамики изменений метилирования импринтированных локусов в опухолях человека, мы предполагаем, что процесс случайного определения вектора изменения характера метилирования опосредован нарушениями копийности участков моноаллельного метилирования ДНК. Причиной равновероятных разнонаправленных изменений моноаллельного метилирования может быть геномный дисбаланс, который может случайным образом приводить к делециям (или приобретенной однородительской дисомии) либо метилированного, либо неметилированного аллеля. Aim: to evaluate changes in the methylation status of cytosine residues in CpG islands, monoallelically methylated in the norm, in samples of malignant breast tumors. Methods. To determine CpG dinucleotides monoallelically methylated in tumor and normal breast tissues, we used the results of Xmal-RRBS genome-wide bisulfite sequencing obtained earlier. Changes in monoallelic methylation in tumors were visualized using histograms for different breast methylotypes. Results. In the genomes of moderately methylated tumors, normally methylated CpG dinucleotides have a tendency to an almost equiprobable methylation change to both the unmethylated and fully methylated states. In the genomes of hypermethylated tumors, normally monoallelically methylated CpG dinucleotides more often change their state to fully methylated. Conclusions. The observed nature of the changes suggests that the dynamics is dictated in moderately methylated tumors by processes that do not determine their vector, and in hypermethylated tumors, additionally, by a directed process that increases the methylation level of CpG dinucleotides. By analogy with the previously published results of a study of the dynamics of changes in methylation of imprinted loci in human tumors, we assume that the process of random determination of the vector of methylation changes is mediated by copy number aberrations at the regions of monoallelic DNA methylation. The reason for the equally probable bidirectional changes in monoallelic methylation may be a genomic imbalance that can randomly lead to deletions (or acquired uniparental disomy) of either the methylated or unmethylated allele.

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SNP-guided identification of monoallelic DNA-methylation events from enrichment-based sequencing data

Abstract: ABSTRACT

Cited by 3 publications

References 52 publications

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

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

A Comprehensive Overview of Genomic Imprinting in Breast & Its Deregulation in Cancer

Alterations of monoallelic DNA methylation in breast cancer

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