An imprinted antisense RNA overlaps UBE3A and a second maternally expressed transcript

Rougeulle, Claire; Cardoso, Carlos; Fontés, Michel; Colleaux, Laurence; Lalande, Marc

doi:10.1038/ng0598-15

Cited by 285 publications

(172 citation statements)

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“…A role for noncoding RNAs is implicated in the regulation of imprinted genes due to the preponderance of these transcribed sequences located in imprinted domains and empirical data suggesting their importance (26,27,(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42). For example, the genes Delta, Drosophila homologue-like 1 (DLK1) and maternally expressed gene 3 (MEG3) in the imprinted domain on human chromosome 14 bear remarkable similarity to the IGF2/H19 domain in terms of the genomic organization and putative regulatory features (43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

Frequent IGF2/H19 Domain Epigenetic Alterations and Elevated IGF2 Expression in Epithelial Ovarian Cancer

Murphy

Huang

Wen

et al. 2006

Molecular Cancer Research

125

103

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Overexpression of the imprinted insulin-like growth factor-II (IGF2) is a prominent characteristic of gynecologic malignancies. The purpose of this study was to determine whether IGF2 loss of imprinting (LOI), aberrant H19 expression, and/or epigenetic deregulation of the IGF2/H19 imprinted domain contributes to elevated IGF2 expression in serous epithelial ovarian tumors. IGF2 LOI was observed in 5 of 23 informative serous epithelial ovarian cancers, but this did not correlate with elevated expression of IGF2 H19 RNA expression levels were also found not to correlate with IGF2 transcript levels. However, we identified positive correlations between elevated IGF2 expression and hypermethylation of CCCTC transcription factor binding sites 1 and 6 at the H19 proximal imprint center (P = 0.05 and 0.02, respectively). Hypermethylation of CCCTC transcription factor sites 1 and 6 was observed more frequently in cancer DNA compared with lymphocyte DNA obtained from women without malignancy (P < 0.0001 for both sites 1 and 6). Ovarian cancers were also more likely to exhibit maternal allele-specific hypomethylation upstream of the imprinted IGF2 promoters when compared with normal lymphocyte DNA (P = 0.004). This is the same region shown previously to be hypomethylated in colon cancers with IGF2 LOI, but this was not associated with LOI in ovarian cancers. Elevated IGF2 expression is a frequent event in serous ovarian cancer and this occurs in the absence of IGF2 LOI. These data indicate that the epigenetic changes observed in these cancers at the imprint center may contribute to IGF2 overexpression in a novel mechanistic manner. (Mol Cancer Res 2006;4(4):283 -92)

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Section: Discussionmentioning

confidence: 99%

Frequent IGF2/H19 Domain Epigenetic Alterations and Elevated IGF2 Expression in Epithelial Ovarian Cancer

Murphy

Huang

Wen

et al. 2006

Molecular Cancer Research

125

103

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“…44 Because no differentially methylated promoter region is present in UBE3A, it has been proposed that the imprinted expression of UBE3A may be regulated indirectly through a paternally expressed antisense transcript. 93 Runte et al 94 have shown that a long SNURF-SNRPN sense/ UBE3A antisense RNA transcript exists in the AS/PWS region, starting from the SNURF-SNRPN imprinting center (IC) and extending more than 460 kb to at least the 5Ј end of UBE3A. It has been proposed that this UBE3A antisense transcript blocks paternal UBE3A gene expression.…”

Section: Ubiquitin Ligase E3a (Ube3a)mentioning

confidence: 99%

Clinical and genetic aspects of Angelman syndrome

Williams

Driscoll

Dagli

2010

Genetics in Medicine

281

235

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“…These can be generated by processing longer double-stranded RNAs formed by complementary pairing of mRNAs and long antisense transcripts due to bidirectional transcription at the same locus [Morris, 2009]. The presence of long ncRNAs overlapping (at least in part) critical mRNAs has been proven in several imprinted loci such as those of Angelman and Beckwith-Wiedemann syndromes [Rougeulle et al, 1998;Lee et al, 1999] as well as those of Fragile X H3K4, lysine 4 on histone 3; H3K9, lysine 9 on histone 3; H3K14, lysine 14 on histone 3; H3K27, lysine 27 on histone 3; H3K36, lysine 36 on histone 3; H3K20, lysine 20 on histone 3; H2BK5, lysine 5 on histone 2B. A similar regulatory role is played by miRNAs, short endogenous ncRNAs that adopt a hairpin conformation due to internal base complementarity, which regulate a large variety of biological functions [Wang et al, 2012].…”

Section: Rna Transcriptsmentioning

confidence: 99%

“…These can be generated by processing longer double-stranded RNAs formed by complementary pairing of mRNAs and long antisense transcripts due to bidirectional transcription at the same locus [Morris, 2009]. The presence of long ncRNAs overlapping (at least in part) critical mRNAs has been proven in several imprinted loci such as those of Angelman and Beckwith-Wiedemann syndromes [Rougeulle et al, 1998;Lee et al, 1999] as well as those of Fragile X [Ladd et al, 2007;Chen et al, 2008;De Biase et al, 2009]. It is assumed that double-stranded RNAs are processed by the RNAi machinery into siRNAs that induce either degradation of complementary mRNAs (post-transcriptional gene silencing) or cause RNA-mediated DNA methylation (transcriptional gene silencing).…”

Section: Rna Transcriptsmentioning

confidence: 99%

Epigenetics, fragile X syndrome and transcriptional therapy

Tabolacci

Chiurazzi

2013

American J of Med Genetics Pt A

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Epigenetics refers to the study of heritable changes in gene expression that occur without a change in DNA sequence. Epigenetic mechanisms therefore include all transcriptional controls that determine how genes are expressed during development and differentiation, but also in individual cells responding to environmental stimuli. The purpose of this review is to examine the basic principles of epigenetic mechanisms and their contribution to human disorders with a particular focus on fragile X syndrome (FXS), the most common monogenic form of developmental cognitive impairment. FXS represents a prototype of the so-called repeat expansion disorders due to "dynamic" mutations, namely the expansion (known as "full mutation") of a CGG repeat in the 5 0 UTR of the FMR1 gene. This genetic anomaly is accompanied by epigenetic modifications (mainly DNA methylation and histone deacetylation), resulting in the inactivation of the FMR1 gene. The presence of an intact FMR1 coding sequence allowed pharmacological reactivation of gene transcription, particularly through the use of the DNA demethylating agent 5 0 -aza-2 0 -deoxycytydine and/or inhibitors of histone deacetylases. These treatments suggested that DNA methylation is dominant over histone acetylation in silencing the FMR1 gene. The importance of DNA methylation in repressing FMR1 transcription is confirmed by the existence of rare unaffected males carrying unmethylated full mutations. Finally, we address the potential use of epigenetic approaches to targeted treatment of other genetic conditions. Ó 2013 Wiley Periodicals, Inc.Key words: fragile X syndrome; epigenetics; transcriptional therapy INTRODUCTION When in 1942 Conrad H. Waddington coined the term "epigenetics," the exact nature of genes and their role in heredity and in transcriptional regulation was not known; he used it as a conceptual model of how genes might interact with their surroundings to produce a phenotype [Waddington, 1942]. The term is a portmanteau of the words epigenesis (differentiation of cells from their initial totipotent state in embryonic development) and genetics. Only in 2008 at a Cold Spring harbor meeting, consensus was reached on the definition of epigenetic trait, as "stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence" [Berger et al., 2009]. The greek prefix epi-refers to features that are "on top of" genetics, that is, all those stable but reversible changes to DNA, RNA and proteins that regulate gene expression and allow cells with the same DNA to do different things at different times.Broadly speaking, epigenetic mechanisms include all transcriptional controls that regulate gene expression, whether during development and differentiation or in mature cells responding to the environment. Epigenetic changes can be inherited (e.g., imprinting) and be relatively stable (e.g., chromosome X inactivation), but are often rapidly imposed or removed on a given locus according to cell needs. Four major layers of epigenetic controls have ...

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An imprinted antisense RNA overlaps UBE3A and a second maternally expressed transcript

Cited by 285 publications

References 8 publications

Frequent IGF2/H19 Domain Epigenetic Alterations and Elevated IGF2 Expression in Epithelial Ovarian Cancer

Frequent IGF2/H19 Domain Epigenetic Alterations and Elevated IGF2 Expression in Epithelial Ovarian Cancer

Clinical and genetic aspects of Angelman syndrome

Epigenetics, fragile X syndrome and transcriptional therapy

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