<i>Igf2</i> imprinting does not require its own DNA methylation or <i>H19</i> RNA

Jones, Beverly K.; Levorse, John; Tilghman, Shirley M.

doi:10.1101/gad.12.14.2200

Cited by 93 publications

(57 citation statements)

References 49 publications

(63 reference statements)

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“…Similar to the compensatory expression changes observed in our mutant mice, mutations that attenuated adult ␤-globin expression were accompanied by an increase in the expression of ⑀-globin (Foley and Engel 1992). Recent experiments by Jones and colleagues indicate that the competition by H19 and Igf2 promoters for the endoderm enhancers may not be mediated strictly by the promoters and DMD alone (Jones et al 1998a). In experiments in which the H19 transcriptional unit was replaced with the luciferase gene, luciferase was expressed at variable levels on the paternal allele, whereas the expression and imprinting of Igf2 was maintained at wild-type levels.…”

Section: Discussionsupporting

confidence: 54%

Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2

Thorvaldsen

Duran²,

Bartolomei³

1998

Genes Dev.

613

537

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Differentially methylated sequences associated with imprinted genes are proposed to control genomic imprinting. A 2-kb region located 5 to the imprinted mouse H19 gene is hypermethylated on the inactive paternal allele throughout development. To determine whether this differentially methylated domain (DMD) is required for imprinted expression at the endogenous locus, we have generated mice harboring a 1.6-kb targeted deletion of the DMD and assayed for allelic expression of H19 and the linked, oppositely imprinted Igf2 gene. H19 is activated and Igf2 expression is reduced when the DMD deletion is paternally inherited; conversely, upon maternal transmission of the mutation, H19 expression is reduced and Igf2 is activated. Consistent with the DMD's hypothesized role of setting up the methylation imprint, the mutation also perturbs allele-specific methylation of the remaining H19 sequences. In conclusion, these experiments show that the H19 hypermethylated 5 flanking sequences are required to silence paternally derived H19.Additionally, these experiments demonstrate a novel role for the DMD on the maternal chromosome where it is required for the maximal expression of H19 and the silencing of Igf2. Thus, the H19 differentially methylated sequences are required for both H19 and Igf2 imprinting.

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Section: Discussionsupporting

confidence: 54%

Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2

Thorvaldsen

Duran²,

Bartolomei³

1998

Genes Dev.

613

537

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“…Although the functional significance of the unusual maternal chromatin organization is unknown, this element upstream of the mouse H19 gene can act as a silencer in transgenic flies (34) and insulates the Igf2 gene from enhancers that are downstream of the H19 gene in the mouse (21,27,51,58). The boundary-insulator property of this element is observed on the maternal allele in the mouse, which is unmethylated in this region (53), as is the Drosophila genome (54).…”

Section: Discussionmentioning

confidence: 99%

“…This clearly demonstrated that sequences upstream and/or within H19 are also necessary for the paternal expression of these two neighboring imprinted genes (31). Two subsequent targeted deletions of H19 did not include upstream sequences and had only minor effects on Igf2 expression (27,42). Recently, a targeted deletion was performed in which a 1.6-kb element corresponding to the core region of paternal methylation upstream of H19 was deleted.…”

mentioning

confidence: 99%

“…When paternally transmitted, this deletion led to activation of the paternal H19 gene whereas maternal transmission resulted in activation of the maternal Igf2 gene (51). Based on these targeting experiments, it has been proposed that one of the functions of this upstream element is to insulate the maternal Igf2 gene from enhancers located downstream of H19 (27,51). This postulate is supported by the finding that when endoderm-specific enhancers downstream of the H19 gene were moved to a position be-tween Igf2 and H19 (at a location upstream of the proposed boundary element), the Igf2 gene became derepressed (58).…”

mentioning

confidence: 99%

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Parental Allele-Specific Chromatin Configuration in a Boundary–Imprinting-Control Element Upstream of the Mouse H19 Gene

Khosla

Aitchison

Gregory

et al. 1999

Molecular and Cellular Biology

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The mouse H19 gene is expressed from the maternal chromosome exclusively. A 2-kb region at 2 to 4 kb upstream of H19 is paternally methylated throughout development, and these sequences are necessary for the imprinted expression of both H19 and the 5 -neighboring Igf2 gene. In particular, on the maternal chromosome this element appears to insulate the Igf2 gene from enhancers located downstream of H19. We analyzed the chromatin organization of this element by assaying its sensitivity to nucleases in nuclei. Six DNase I hypersensitive sites (HS sites) were detected on the unmethylated maternal chromosome exclusively, the two most prominent of which mapped 2.25 and 2.75 kb 5 to the H19 transcription initiation site. Five of the maternal HS sites were present in expressing and nonexpressing tissues and in embryonic stem (ES) cells. They seem, therefore, to reflect the maternal origin of the chromosome rather than the expression of H19. A sixth maternal HS site, at 3.45 kb upstream of H19, was detected in ES cells only. The nucleosomal organization of this element was analyzed in tissues and ES cells by micrococcal nuclease digestion. Specifically on the maternal chromosome, an unusual and strong banding pattern was obtained, suggestive of a nonnucleosomal organization. From our studies, it appears that the unusual chromatin organization with the presence of HS sites (maternal chromosome) and DNA methylation (paternal chromosome) in this element are mutually exclusive and reflect alternate epigenetic states. In addition, our data suggest that nonhistone proteins are associated with the maternal chromosome and that these might be involved in its boundary function.

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“…In this way, the insulator sequence upstream of H19 comprises an "imprinting center" that regulates the reciprocal expression of H19 and Igf2. Although H19 is conserved among mammals and highly expressed in embryos, studies carried out over the last 15 yr indicate that the H19 transcript itself has no apparent role in the imprinted expression of its neighboring genes (Jones et al 1998) and is also not necessary for normal development in mice (Ripoche et al 1997). The chromosomal region containing H19 has also been associated with tumor suppressor activity, and the expression pattern of H19 RNA in several cancer cell types differs from neighboring nonmalignant cells (see "Regulatory RNAs Implicated in Complex Diseases: Dark Side of RNA" below).…”

Section: Igf2/h19 Locusmentioning

confidence: 99%

Eukaryotic regulatory RNAs: an answer to the ‘genome complexity’ conundrum

Prasanth¹,

Spector²

2007

Genes Dev.

364

305

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A large portion of the eukaryotic genome is transcribed as noncoding RNAs (ncRNAs). While once thought of primarily as "junk," recent studies indicate that a large number of these RNAs play central roles in regulating gene expression at multiple levels. The increasing diversity of ncRNAs identified in the eukaryotic genome suggests a critical nexus between the regulatory potential of ncRNAs and the complexity of genome organization. We provide an overview of recent advances in the identification and function of eukaryotic ncRNAs and the roles played by these RNAs in chromatin organization, gene expression, and disease etiology.

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Igf2 imprinting does not require its own DNA methylation or H19 RNA

Cited by 93 publications

References 49 publications

Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2

Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2

Parental Allele-Specific Chromatin Configuration in a Boundary–Imprinting-Control Element Upstream of the Mouse H19 Gene

Eukaryotic regulatory RNAs: an answer to the ‘genome complexity’ conundrum

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