CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus

Filippova, Galina N.; Thienes, Cortlandt P.; Penn, Bennett H.; Cho, Diane H.; Hu, Ying; Moore, James M.; Klesert, Todd R.; Lobanenkov, Victor; Tapscott, Stephen J.

doi:10.1038/ng570

Cited by 292 publications

(291 citation statements)

References 43 publications

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“…Thus, they provide the plasticity required to respond to developmental and environmental cues. As expected, in light of all these functions it is not surprising to find clear connections between insulator mutations and human diseases as illustrated in a congenital form of myotonic dystrophy associated with a loss of the function of the DM1 insulator (Filippova et al, 2001). Although all the roles reported above have been clearly attributed to insulators, it is nevertheless intriguing to find in some cases that deletion of some insulator sequences is not lethal and sometimes has no obvious phenotype.…”

Section: Resultsmentioning

confidence: 93%

Insulators are fundamental components of the eukaryotic genomes

Brasset

Vaury

2005

Heredity

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The properties of cis-regulatory elements able to influence gene transcription over large distances have led to the hypothesis that elements called insulators should exist to limit the action of enhancers and silencers. During the last decades, insulators have been identified in many eukaryotes from yeast to human. Insulators possess two main properties: (i) they can block enhancer-promoter communication ('enhancer blocker activity'), and (ii) they can prevent the spread of repressive chromatin ('barrier activity'). This review focuses on recent studies designed to elucidate the molecular mechanisms of the insulator function, and gives an overview of the critical role of insulators in nuclear organization and functional identity of chromatin. Heredity (2005) 94, 571-576.

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Section: Resultsmentioning

confidence: 93%

Insulators are fundamental components of the eukaryotic genomes

Brasset

Vaury

2005

Heredity

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“…7). Two other CTCF-dependent insulators, FII and DM1 site 1 (34,35), have been reported to comprise a Sp1-binding site that is known as a cis-acting regulator of the unmethylated state within a CpG island (21,28), although the actual function of the site is unknown. Here, we suggest that the CTCF-binding site may be necessary but not sufficient for efficient enhancer blocking activity of the CTCF-dependent insulator that functions on the genome undergoing or previously modified by de novo methylation.…”

Section: Cis-acting Element Directing Demethylation Within the Icr-mentioning

confidence: 99%

A Dyad Oct-binding Sequence Functions as a Maintenance Sequence for the Unmethylated State within theH19/Igf2-imprinted Control Region

Hori

Nakano

Takeuchi

et al. 2002

Journal of Biological Chemistry

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DNA methylation of an imprinted control region (ICR) directs the allele-specific and reciprocal expression of the mouse H19 and the insulin-like growth factor 2 (Igf2) genes, mediated by controlling enhancer access. The ICR shows enhancer blocking activity through CTCF binding to an unmethylated sequence. The unmethylated state of the maternal ICR is maintained throughout development after establishment in the germ line; however, little is known of the molecular mechanisms that regulate DNA methylation. Hence, in this study we show that a dyad Oct-binding sequence (DOS) in the ICR mediates the demethylation of low-density methylation but not hypermethylation and is required to maintain the unmethylated state against the tendency for de novo methylation within the ICR in the embryonic carcinoma cell line P19. Furthermore, we also reveal that the unmethylated state of at least one CTCF-binding site within the ICR is under the control of DOS. Our results suggest that the ICR, as a CTCF-dependent insulator, requires DOS as well as CTCF-binding sites and that DOS maintains the maternal specific unmethylated state of the ICR at postimplantation stages.Mouse H19 and Igf2 (insulin-like growth factor 2) genes are ϳ70 kb distant from each other and are a set of imprinted genes that are reciprocally expressed only from the maternal and paternal allele, respectively, in identical tissues with the same timing. Monoallelic expression of both genes depends on differential methylation of an imprinted control region (ICR), 1 located 2-4-kb upstream of the H19 gene, that is hypermethylated in the paternal chromosome but unmethylated in the maternal chromosome. Genomic deletions of the ICR result in activation of the normally silent maternal Igf2 and paternal H19 genes in liver, gut, kidney, heart, skeletal muscle, and lung (1, 2). Additionally, deletion of endodermal enhancers downstream from the H19 gene results in loss of maternal expression of H19 and paternal Igf2 in liver, gut, and kidney (3). These results suggest that the paternal ICR represses H19 expression and that the maternal ICR represses expression of the distant Igf2 through enhancer blocking activity at least in liver, gut and kidney. In fact, recent reports revealed that a 1.2-kb portion of the methylated ICR in the paternal chromosome functioned as a transcriptional silencer in endodermal tissue (4) and that the unmethylated ICR functioned as a CTCF-dependent insulator (1, 5-7). Methylation of the CTCFbinding site inhibited binding of the CTCF protein (5, 6). Moreover, the binding of CTCF in mouse fetal liver was observed only on the maternal ICR (7). These observations suggest that the enhancer blocking activity is repressed on the hypermethylated paternal ICR, which enables association between downstream enhancers and the Igf2 promoter. Thus, the methylation status of the ICR is a crucial factor for monoallelic expression in both genes.The unmethylated state of the maternal ICR is established in the germ line and maintained during development (8 -10), although...

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“…Moreover, in the 3'UTR region of the DMPK gene, CTG repeats are flanked by CTCF binding-site. 50 CTCF restricts the extent of antisense transcription and constrains the spreading of heterochromatin from the triplets. 50,51 Thus, the vertebrate insulator protein might have a bivalent role around the triplets by initiating, activating and restricting bidirectional transcription, which in turn enhances and…”

Section: Is the Molecular Mechanism Of Fshd Relevant For Other Patholmentioning

confidence: 99%

“…For instance, microdeletion or microduplications of the CTCF sites at the IGF2/H19 locus are associated with some cases of non syndromic Wilm tumors. 49 Also, CTCF flanks CTG/CAG trinucleotide repeats at several disease-associated loci, such as the DM1 locus implicated in myotonic dystrophy, an autosomal dominant multisystemic disorder characterized by myotonia, muscular dystrophy, cataracts, hypogonadism, cardiac conduction anomaly and diabetes mellitus, 50,51 which is caused by a CTG repeat expansion. The physiopathology of DM1 is not fully elicited and may be linked to a complex mechanism involving chromatin changes and CTCF.…”

Section: Is the Molecular Mechanism Of Fshd Relevant For Other Patholmentioning

confidence: 99%