Sequence conservation and variability of imprinting in the Beckwith-Wiedemann syndrome gene cluster in human and mouse

Paulsen, Martina; El‐Maarri, Osman; Engemann, Sabine; Strödicke, Martin; Franck, Olivia; Davies, Karen; Reinhardt, Richard; Reik, Wolf; Walter, Jörn

doi:10.1093/hmg/9.12.1829

Cited by 120 publications

(77 citation statements)

References 65 publications

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“…The mouse and human Kcnq1ot1/KCNQ1OT1 domains possess a high degree of synteny (Paulsen et al, 1998;Engemann et al, 2000;Onyango et al, 2000;Paulsen et al, 2000;Yatsuki et al, 2000). Both domains are ~1 Mb and the maternal ICR is methylated and the Kcnq1ot1/KCNQ1OT1 ncRNA is expressed from the paternal allele Barlow and Bartolomei, 2007).…”

Section: Kcnq1ot1 Length and Functionmentioning

confidence: 99%

Depletion of Kcnq1ot1 non-coding RNA does not affect imprinting maintenance in stem cells

et al. 2011

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SUMMARYTo understand the complex regulation of genomic imprinting it is important to determine how early embryos establish imprinted gene expression across large chromosomal domains. Long non-coding RNAs (ncRNAs) have been associated with the regulation of imprinting domains, yet their function remains undefined. Here, we investigated the mouse Kcnq1ot1 ncRNA and its role in imprinted gene regulation during preimplantation development by utilizing mouse embryonic and extra-embryonic stem cell models. Our findings demonstrate that the Kcnq1ot1 ncRNA extends 471 kb from the transcription start site. This is significant as it raises the possibility that transcription through downstream genes might play a role in their silencing, including Th, which we demonstrate possesses maternal-specific expression during early development. To distinguish between a functional role for the transcript and properties inherent to transcription of long ncRNAs, we employed RNA interference-based technology to deplete Kcnq1ot1 transcripts. We hypothesized that post-transcriptional depletion of Kcnq1ot1 ncRNA would lead to activation of normally maternal-specific protein-coding genes on the paternal chromosome. Post-transcriptional short hairpin RNA-mediated depletion in embryonic stem, trophoblast stem and extra-embryonic endoderm stem cells had no observable effect on the imprinted expression of genes within the domain, or on Kcnq1ot1 imprinting center DNA methylation, although a significant decrease in Kcnq1ot1 RNA signal volume in the nucleus was observed. These data support the argument that it is the act of transcription that plays a role in imprint maintenance during early development rather than a post-transcriptional role for the RNA itself.

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Section: Kcnq1ot1 Length and Functionmentioning

confidence: 99%

Depletion of Kcnq1ot1 non-coding RNA does not affect imprinting maintenance in stem cells

et al. 2011

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“…A remarkable feature of imprinted genes is that they are physically linked in clusters with other imprinted genes and do show unique patterns of sequence conservation (Hutter et al, 2010). The DNA sequence environment of imprinted genes is usually rich in CpG islands (CGI), repetitive elements and transcription factor binding sites (TFBS) (Paulsen et al, 2000;Neumann et al, 1995). These features are being used to analyze known and putative imprinted genes (Khatib et al, 2007;Luedi et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

DNA Sequence Characteristics and Phylogenetics of Putative Imprinted Genes on Bovine Chromosome 29

Bamidele¹,

Omitogun²,

Imumorin³

2015

JAS

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Cattle are important livestock species with huge genetic resource for food security, agriculture and livelihoods. Over 60% of its genes are homologous to all mammalian species which creates a molecular basis for conducting comparative genomic analysis. Genomic imprinting has been implicated in a variety of biological functions and so identification of new or verification of known imprinted genes in livestock species is of high agricultural and biomedical importance. Fourteen (14) putative imprinted genes on bovine chromosome 29 (Bta 29) as well as the human (Hg 11) and mouse (Mm 7) orthologs were computationally characterized with respect to the CpG islands (CGI), transcription factor binding elements and sequence motif. Phylogenetic analysis was conducted across the three species for each of the genes identified to have promoter CGI. Promoter CGI were identified in ASCL2, TSSC4, CDKN1C, KCNQ1, PHLDA2 and NAP1L4. The promoter CGI were enriched with CpG containing transcription factor binding sites. Generally, it was observed that cattle was more closely related to human than mouse and that natural selection was the force driving the evolutionary change between the three species. Protein kinase motifs involved in phosphorylation were identified in the amino-acid sequences of ASCL2, TSSC4, PHLDA2 and NAP1L4. Our results suggest the post-translation regulation of imprinting and that the predicted promoter CGI can be assayed to determine molecular function, gene expression and DNA methylation status of the bovine putative imprinted genes.

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“…The Kcnq1 imprinted domain lies on distal mouse chromosome 7 and contains one paternally expressed gene, the non-coding RNA Kcnq1ot1, several flanking genes which are paternally repressed in all lineages (we term these ubiquitously imprinted genes) and other flanking genes which are paternally repressed in placental lineages but are not imprinted in embryonic lineages Paulsen et al, 2000). It contains two differentially methylated regions (DMRs): one is a germline imprint which acts as the imprinting centre (IC2) and contains the promoter of the non-coding Kcnq1ot1 gene; the other is a secondary imprint upstream of the cell cycle regulator Cdkn1c which is not established until postimplantation stages of development (Bhogal et al, 2004;Engemann et al, 2000;Fitzpatrick et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic dynamics of theKcnq1imprinted domain in the early embryo

et al. 2006

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The mouse Kcnq1 imprinted domain is located on distal chromosome 7 and contains several imprinted genes that are paternally repressed. Repression of these genes is regulated by a non-coding antisense transcript, Kcnq1ot1, which is paternally expressed. Maternal repression of Kcnq1ot1 is controlled by DNA methylation originating in the oocyte. Some genes in the region are imprinted only in the placenta, whereas others are imprinted in both extra-embryonic and embryonic lineages. Here, we show that Kcnq1ot1 is paternally expressed in preimplantation embryos from the two-cell stage, and that ubiquitously imprinted genes proximal to Kcnq1ot1 are already repressed in blastocysts, ES cells and TS cells. Repressive histone marks such as H3K27me3 are present on the paternal allele of these genes in both ES and TS cells. Placentally imprinted genes that are distal to Kcnq1ot1, by contrast, are not imprinted in blastocysts, ES or TS cells. In these genes, paternal silencing and differential histone marks arise during differentiation of the trophoblast lineage between E4.5 and E7.5. Our findings show that the dynamics during preimplantation development of gene inactivation and acquisition of repressive histone marks in ubiquitously imprinted genes of the Kcnq1 domain are very similar to those of imprinted X inactivation. By contrast, genes that are only imprinted in the placenta, while regulated by the same non-coding RNA transcript Kcnq1ot1, undergo epigenetic inactivation during differentiation of the trophoblast lineage. Our findings establish a model for how epigenetic gene silencing by non-coding RNA may depend on distance from the non-coding RNA and on lineage and differentiation specific factors.

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Sequence conservation and variability of imprinting in the Beckwith-Wiedemann syndrome gene cluster in human and mouse

Cited by 120 publications

References 65 publications

Depletion of Kcnq1ot1 non-coding RNA does not affect imprinting maintenance in stem cells

Depletion of Kcnq1ot1 non-coding RNA does not affect imprinting maintenance in stem cells

DNA Sequence Characteristics and Phylogenetics of Putative Imprinted Genes on Bovine Chromosome 29

Epigenetic dynamics of theKcnq1imprinted domain in the early embryo

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