A Screen for Retrotransposed Imprinted Genes Reveals an Association between X Chromosome Homology and Maternal Germ-Line Methylation

Wood, Andrew J.; Roberts, Roland G.; Monk, David; Moore, Gudrun E.; Schulz, Reiner; Oakey, Rebecca J.

doi:10.1371/journal.pgen.0030020

Cited by 107 publications

(113 citation statements)

References 52 publications

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“…This suggests that they encode proteins with functions in the oocyte, or the preimplantation embryo, and the activity of these transcription units therefore may have provided the opportunity for imprinting to arise. It has been proposed that imprinted domains could evolve through insertion of CpG-rich elements, such as retroposons (Wood et al 2007), into transcription units active in oocytes, and this is fully consistent with our model. Such events could be the origin of DMRs such as Air and KvDMR1, which became the promoters for long, noncoding RNAs that subsequently came to orchestrate domain-wide monoallelic expression.…”

Section: Oocyte Transcription Units and The Evolution Of Imprinted Locisupporting

confidence: 91%

“…This is supported by the fact that most maternal germline DMRs are within transcription units and by the intronic location of imprinted retrotransposons (Wood et al 2007). Indeed, 15 out of the 17 characterized maternal germline DMRs are in the introns of the genes they regulate (e.g., Igf2r) or, if at promoters, are downstream from alternative transcription start sites (e.g., Grb10) (Table 1; see below).…”

Section: Transcription Across Dmrs In Oocytes Is a Common Feature Of mentioning

confidence: 97%

“…Many maternal germline DMRs are contained within transcription units, including those at four recently evolved imprinted retrotransposons (Wood et al 2007), and in general, intragenic CGIs are more likely to be methylated than those at promoters (Yamada et al 2004;Illingworth et al 2008). In a transgene study, the Air DMR was appropriately methylated in some mouse lines when located in an intron of an Aprt transgene (Sleutels and Barlow 2001).…”

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confidence: 99%

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Transcription is required for establishment of germline methylation marks at imprinted genes

Chotalia¹,

Smallwood²,

Ruf³

et al. 2009

Genes Dev.

315

306

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Genomic imprinting requires the differential marking by DNA methylation of genes in male and female gametes. In the female germline, acquisition of methylation imprint marks depends upon the de novo methyltransferase Dnmt3a and its cofactor Dnmt3L, but the reasons why specific sequences are targets for Dnmt3a and Dnmt3L are still poorly understood. Here, we investigate the role of transcription in establishing maternal germline methylation marks. We show that at the Gnas locus, truncating transcripts from the furthest upstream Nesp promoter disrupts oocyte-derived methylation of the differentially methylated regions (DMRs). Transcription through DMRs in oocytes is not restricted to this locus but occurs across the prospective DMRs at many other maternally marked imprinted domains, suggesting a common requirement for transcription events. The transcripts implicated here in gametic methylation are protein-coding, in contrast to the noncoding antisense transcripts involved in the monoallelic silencing of imprinted genes in somatic tissues, although they often initiate from alternative promoters in oocytes. We propose that transcription is a third essential component of the de novo methylation system, which includes optimal CpG spacing and histone modifications, and may be required to create or maintain open chromatin domains to allow the methylation complex access to its preferred targets.[Keywords: Genomic imprinting; DNA methylation; oocytes; transcription] Supplemental material is available at http://www.genesdev.org.

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Section: Oocyte Transcription Units and The Evolution Of Imprinted Locisupporting

confidence: 91%

Section: Transcription Across Dmrs In Oocytes Is a Common Feature Of mentioning

confidence: 97%

mentioning

confidence: 99%

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Transcription is required for establishment of germline methylation marks at imprinted genes

Chotalia¹,

Smallwood²,

Ruf³

et al. 2009

Genes Dev.

315

306

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“…Although attributes such as tandem repeats were implicated [24], and some evidence for 'imprinting signals' was provided by transgenic experiments [25,26], the existence of discrete sequence elements for the specification of gDMR methylation remains in doubt [19]. This may explain the rather limited success of purely sequence-based predictions of imprinted genes [27,28].…”

Section: Introductionmentioning

confidence: 99%

New insights into establishment and maintenance of DNA methylation imprints in mammals

Kelsey

Feil

2013

Phil. Trans. R. Soc. B

185

166

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Fundamental to genomic imprinting in mammals is the acquisition of epigenetic marks that differ in male and female gametes at ‘imprinting control regions’ (ICRs). These marks mediate the allelic expression of imprinted genes in the offspring. Much has been learnt about the nature of imprint marks, the times during gametogenesis at which they are laid down and some of the factors responsible especially for DNA methylation. Recent work has revealed that transcription and histone modifications are critically involved in DNA methylation acquisition, and these findings allow us to propose rational models for methylation establishment. A completely novel perspective on gametic DNA methylation has emerged from epigenomic profiling. Far more differentially methylated loci have been identified in gametes than known imprinted genes, which leads us to revise the notion that methylation of ICRs is a specifically targeted process. Instead, it seems to obey default processes in germ cells, giving rise to distinct patterns of DNA methylation in sperm and oocytes. This new insight, together with the identification of proteins that preserve DNA methylation after fertilization, emphasizes the key role played by mechanisms that selectively retain differential methylation at imprinted loci during early development. Addressing these mechanisms will be essential to understanding the specificity and evolution of genomic imprinting.

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“…In mouse, five imprinted genes (Mcts2, Nap1l5, U2af1-rs1, Inpp5f_v2, and Peg12) are known to have arisen from retrotransposition. [9][10][11] This phenomenon can also be observed in the human genome for a number of genes, e.g., MAGEL2, MKRN3, NDN, and NPAPA1. 9,[12][13][14] In the case of RB1, a differentially methylated CpG island (CpG85), which is part of a retrocopy (PPP1R26P1) and located in intron 2, is responsible for imprinting of the human RB1 gene.…”

Section: Introductionmentioning

confidence: 75%

Genome-wide methylation analysis of retrocopy-associated CpG islands and their genomic environment

et al. 2016

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Gene duplication by retrotransposition, i.e., the reverse transcription of an mRNA and integration of the cDNA into the genome, is an important mechanism in evolution. Based on whole-genome bisulfite sequencing of monocyte DNA, we have investigated the methylation state of all CpG islands (CGIs) associated with a retrocopy (n D 1,319), their genomic environment, as well as the CGIs associated with the ancestral genes. Approximately 10% of retrocopies are associated with a CGI. Whereas almost all CGIs of the human genome are unmethylated, 68% of the CGIs associated with a retrocopy are methylated. In retrocopies resulting from multiple retrotranspositions of the same ancestral gene, the methylation state of the CGI often differs. There is a strong positive correlation between the methylation state of the CGI/ retrocopy and their genomic environment, suggesting that the methylation state of the integration site determined the methylation state of the CGI/retrocopy, or that methylation of the retrocopy by a host defense mechanism has spread into the adjacent regions. Only a minor fraction of CGI/retrocopies (n D 195) has intermediate methylation levels. Among these, the previously reported CGI/retrocopy in intron 2 of the RB1 gene (PPP1R26P1) as well as the CGI associated with the retrocopy RPS2P32 identified in this study carry a maternal methylation imprint. In conclusion, these findings shed light on the evolutionary dynamics and constraints of DNA methylation.

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A Screen for Retrotransposed Imprinted Genes Reveals an Association between X Chromosome Homology and Maternal Germ-Line Methylation

Cited by 107 publications

References 52 publications

Transcription is required for establishment of germline methylation marks at imprinted genes

Transcription is required for establishment of germline methylation marks at imprinted genes

New insights into establishment and maintenance of DNA methylation imprints in mammals

Genome-wide methylation analysis of retrocopy-associated CpG islands and their genomic environment

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