Genomic imprinting mechanisms in embryonic and extraembryonic mouse tissues - PubMed (original) (raw)
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Genomic imprinting mechanisms in embryonic and extraembryonic mouse tissues
Q J Hudson et al. Heredity (Edinb). 2010 Jul.
Abstract
Imprinted genes in mice and humans mainly occur in clusters that are associated with differential DNA methylation of an imprint control element (ICE) and at least one nonprotein-coding RNA (ncRNA). Imprinted gene silencing is achieved by parental-specific insulator activity of the unmethylated ICE mediated by CTCF (CCCTC-binding factor) binding, or by ncRNA expression from a promoter in the unmethylated ICE. In many imprinted clusters, some genes, particularly those located furthest away from the ICE, show imprinted expression only in extraembryonic tissues. Recent research indicates that genes showing imprinted expression only in extraembryonic tissues may be regulated by different epigenetic mechanisms compared with genes showing imprinted expression in extraembryonic tissues and in embryonic/adult tissues. The study of extraembryonic imprinted expression, thus, has the potential to illuminate novel epigenetic strategies, but is complicated by the need to collect tissue from early stages of mouse development, when extraembryonic tissues may be contaminated by maternal cells or be present in limited amounts. Research in this area would be advanced by the development of an in vitro model system in which genetic experiments could be conducted in less time and at a lower cost than with mouse models. Here, we summarize what is known about the mechanisms regulating imprinted expression in mouse extraembryonic tissues and explore the possibilities for developing an in vitro model.
Figures
Figure 1
Three examples of mouse imprinted gene clusters showing imprinted expression in the embryo and/or adult versus placenta. (a) Igf2r cluster: imprinted silencing on the paternal chromosome is initiated by the Airn macro ncRNA. (b) Kcnq1 cluster: imprinted silencing on the paternal chromosome is initiated by the Kcnq1ot1 macro ncRNA. (c) Igf2 cluster: imprinted silencing on the maternal chromosome is initiated by CTCF binding the unmethylated ICE forming an insulator that blocks access to enhancers. Protein-coding genes and ncRNAs showing imprinted expression are shown as pink (maternally expressed) and blue (paternally expressed), with genes showing no parental allelic difference in gray. ICE, imprint control element; M, DNA methylation; and E, enhancer.
Figure 2
Development of mouse extraembryonic cell lineages. Epiblast-derived tissue is shown in red, trophectoderm-derived tissue in blue and primitive endoderm-derived tissue in green.
Figure 3
A summary of published work on imprinted macro ncRNA function in the embryo and in extraembryonic tissues. Genes showing imprinted expression in embryo/adult tissues tend to be close to the ICE that contains the macro ncRNA promoter. DNA methylation is important to maintain imprinted expression in the embryo. In extraembryonic tissues, genes located further away from the ICE/ncRNA promoter will show imprinted expression. DNA methylation may not be required to maintain imprinted expression of genes showing extraembryonic-specific imprinted expression, instead repressive chromatin modifications such as H3K27me3, H2AK119u1 and H3K9me2 that are deposited by polycomb complexes (PRC) and G9A are required to maintain imprinted expression. The macro ncRNA is implicated in recruiting these repressive complexes to extraembryonic-specific imprinted genes. The ncRNA forms a cloud that is larger in extraembryonic tissues and often covers the genes that are silenced (dotted blue line). ICE, imprint control element; M, DNA methylation; and E, enhancer.
Figure 4
Models explaining embryonic and/or adult versus extraembryonic imprinted expression. (a) Insulator model: in the embryo/adult model, CTCF binds the unmethylated ICE allele and acts as an insulator, blocking access of enhancers to Gene A, whereas expression of the more distant Gene B is unaffected. In extraembryonic tissues, the insulator action extends over a greater distance also blocking enhancer access to Gene B. (b) Transcriptional interference model: in the embryo/adult model, transcription of the ncRNA overlaps the promoter of Gene A preventing upregulation of expression on this chromosome. In extraembryonic tissues, expression of the ncRNA disrupts an enhancer interaction with a distant Gene B preventing upregulation of expression on this chromosome. (c) RNA-meditated silencing model: in the embryo/adult model, the ncRNA cloud covers a limited area and the ncRNA recruits repressive chromatin-modifying complexes PRC and G9A to nearby Gene A. In extraembryonic tissues, the ncRNA cloud covers a larger area and recruits repressive chromatin modifiers to both Gene A and the more distant Gene B. ICE, imprint control element; M, DNA methylation; and E, enhancer.
Figure 5
In vitro models to study the imprinting mechanism. ES cells derived from the ICM can be differentiated in vitro providing a model of embryonic imprinted expression. Models of extraembryonic imprinted expression are TS cells derived from trophectoderm and XEN cells derived from primitive endoderm. Differentiation of ES cells into embryoid bodies (EBs) can form tissues expressing markers of visceral endoderm and resembling VYS, suggesting that this system may provide a model of extraembryonic imprinted expression.
References
- Abe K, Niwa H, Iwase K, Takiguchi M, Mori M, Abe SI, et al. Endoderm-specific gene expression in embryonic stem cells differentiated to embryoid bodies. Exp Cell Res. 1996;229:27–34. - PubMed
- Barlow DP, Stoger R, Herrmann BG, Saito K, Schweifer N. The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus. Nature. 1991;349:84–87. - PubMed
- Bartolomei MS, Zemel S, Tilghman SM. Parental imprinting of the mouse H19 gene. Nature. 1991;351:153–155. - PubMed
- Bell AC, Felsenfeld G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature. 2000;405:482–485. - PubMed
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