Antisense Transcription and Heterochromatin at the DM1 CTG Repeats Are Constrained by CTCF

Cho, Diane H.; Thienes, Cortlandt P.; Mahoney, Sarah E.; Analau, Erwin; Filippova, Galina N.; Tapscott, Stephen J.

doi:10.1016/j.molcel.2005.09.002

Cited by 262 publications

(306 citation statements)

References 23 publications

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“…Although in most repeat expansion diseases, the sense strand transcript or its translated protein products are thought to have primacy in disease pathogenesis, discovery of antisense strand transcripts is leading to increasing appreciation of their potential significance in disease pathogenesis (45)(46)(47)(48)(49)(50)(51)56). In FXTAS, antisense strand transcripts, as well as sense strand transcripts, are up-regulated, polyadenylated at the 3′ end, and capped at the 5′ end (47), although only the sense strand is known to generate nuclear inclusions (57).…”

Section: Discussionmentioning

confidence: 99%

“…Recognizing that in several other examples of expanded nucleotide repeat diseases, bidirectional transcription of the repeat has been identified (45)(46)(47)(48)(49)(50)(51), and that a recent study reported antisense transcripts in C9orf72 patient nervous systems (20), we examined C9orf72 patient fibroblasts for accumulation of RNAs transcribed in the antisense direction. Using FISH with LNA probes to the antisense strand of the hexanucleotide repeat GGCCCC, RNA foci were identified in all six fibroblasts from C9orf72 expansion patients tested and were not observed in fibroblasts from three nonaffected individuals (Fig.…”

Section: Antisense Strand Of C9orf72 Is Transcribed and Ggcccc Expanmentioning

confidence: 99%

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Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration

Lagier‐Tourenne

Baughn

Rigo

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

521

573

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Expanded hexanucleotide repeats in the chromosome 9 open reading frame 72 (C9orf72) gene are the most common genetic cause of ALS and frontotemporal degeneration (FTD). Here, we identify nuclear RNA foci containing the hexanucleotide expansion (GGGGCC) in patient cells, including white blood cells, fibroblasts, glia, and multiple neuronal cell types (spinal motor, cortical, hippocampal, and cerebellar neurons). RNA foci are not present in sporadic ALS, familial ALS/FTD caused by other mutations (SOD1, TDP-43, or tau), Parkinson disease, or nonneurological controls. Antisense oligonucleotides (ASOs) are identified that reduce GGGGCC-containing nuclear foci without altering overall C9orf72 RNA levels. By contrast, siRNAs fail to reduce nuclear RNA foci despite marked reduction in overall C9orf72 RNAs. Sustained ASO-mediated lowering of C9orf72 RNAs throughout the CNS of mice is demonstrated to be well tolerated, producing no behavioral or pathological features characteristic of ALS/FTD and only limited RNA expression alterations. Genome-wide RNA profiling identifies an RNA signature in fibroblasts from patients with C9orf72 expansion. ASOs targeting sense strand repeat-containing RNAs do not correct this signature, a failure that may be explained, at least in part, by discovery of abundant RNA foci with C9orf72 repeats transcribed in the antisense (GGCCCC) direction, which are not affected by sense strand-targeting ASOs. Taken together, these findings support a therapeutic approach by ASO administration to reduce hexanucleotide repeat-containing RNAs and raise the potential importance of targeting expanded RNAs transcribed in both directions.E xpanded hexanucleotide repeats in the first intron of the chromosome 9 open reading frame 72 (C9orf72) gene were recently identified (1, 2) as the most common genetic cause of ALS, frontotemporal degeneration (FTD), or concomitant ALS/ FTD (3, 4). The mechanisms by which the expanded repeats cause neurodegeneration are unknown, but leading candidate mechanisms are RNA-mediated toxicity, loss of the C9orf72 gene function (from reduced C9orf72 produced by the allele with the expansion), or a combination of the two.RNA-mediated toxicity from nucleotide repeat expansion was initially described for CUG expansion in the RNA encoded by the DMPK gene in myotonic muscular dystrophy (5). A consensus view is that RNA toxicity plays a crucial role in a variety of repeat expansion disorders (6). A hallmark of these disorders is the accumulation of expanded transcripts into nuclear RNA foci (7). RNAs harboring a long stretch of repeats are thought to fold into stable structures and sequester RNA binding proteins, which, in turn, sets off a molecular cascade leading to neurodegeneration (7). In myotonic dystrophy, sequestration and functional disruption of the muscleblind-like family of RNA binding proteins are associated with specific splicing and expression changes in affected tissues (5,(8)(9)(10)(11)(12).Sequestration of one or more RNA binding proteins into pathological RNA foci has ...

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Section: Discussionmentioning

confidence: 99%

Section: Antisense Strand Of C9orf72 Is Transcribed and Ggcccc Expanmentioning

confidence: 99%

Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration

Lagier‐Tourenne

Baughn

Rigo

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

521

573

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“…The DM1 alleles under study are identical except in sequences at the CTCF-binding sites that contain base substitutions to eliminate CTCF binding (ref. 20; Fig. S5).…”

Section: Detection Of Ctcf Interacting Proteins By Isotope Coded Affimentioning

confidence: 99%

“…To test whether the association of Scc3/SA1 with chromatin directly depended on the presence of CTCF, we analyzed Scc3/SA1 binding at both a normal and a mutated CTCF-dependent insulator element of the human myotonic dystrophy gene DM1 that had been integrated at the same genomic locus in mouse 3T3 cells via recombination-mediated cassette exchange (RMCE; ref. 20). The DM1 alleles under study are identical except in sequences at the CTCF-binding sites that contain base substitutions to eliminate CTCF binding (ref.…”

Section: Detection Of Ctcf Interacting Proteins By Isotope Coded Affimentioning

confidence: 99%

CTCF physically links cohesin to chromatin

Rubio¹,

Reiss

Welcsh³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

449

382

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Cohesin is required to prevent premature dissociation of sister chromatids after DNA replication. Although its role in chromatid cohesion is well established, the functional significance of cohesin's association with interphase chromatin is not clear. Using a quantitative proteomics approach, we show that the STAG1 (Scc3/ SA1) subunit of cohesin interacts with the CCTC-binding factor CTCF bound to the c-myc insulator element. Both allele-specific binding of CTCF and Scc3/SA1 at the imprinted IGF2/H19 gene locus and our analyses of human DM1 alleles containing base substitutions at CTCF-binding motifs indicate that cohesin recruitment to chromosomal sites depends on the presence of CTCF. A large-scale genomic survey using ChIP-Chip demonstrates that Scc3/SA1 binding strongly correlates with the CTCF-binding site distribution in chromosomal arms. However, some chromosomal sites interact exclusively with CTCF, whereas others interact with Scc3/SA1 only. Furthermore, immunofluorescence microscopy and ChIP-Chip experiments demonstrate that CTCF associates with both centromeres and chromosomal arms during metaphase. These results link cohesin to gene regulatory functions and suggest an essential role for CTCF during sister chromatid cohesion. These results have implications for the functional role of cohesin subunits in the pathogenesis of Cornelia de Lange syndrome and Roberts syndromes.cohesion ͉ transcription ͉ insulator ͉ centromere ͉ metaphase

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“…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%

D4Z4as a prototype of CTCF and lamins-dependent insulator in human cells

Ottaviani

Schluth-Bolard

Gilson

et al. 2010

Nucleus

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Antisense Transcription and Heterochromatin at the DM1 CTG Repeats Are Constrained by CTCF

Cited by 262 publications

References 23 publications

Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration

Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration

CTCF physically links cohesin to chromatin

D4Z4as a prototype of CTCF and lamins-dependent insulator in human cells

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