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Three-dimensional chromatin interactions remain stable upon CAG/CTG repeat expansion

ABSTRACT: Three-dimensional chromatin interactions remain stable upon CAG/CTG repeat expansion

PROVIDER: PRJNA623390 | ENA |

REPOSITORIES: ENA

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Three-dimensional chromatin interactions remain stable upon CAG/CTG repeat expansion

Project description:Expanded CAG/CTG repeats underlie thirteen neurological disorders, including myotonic dystrophy type 1 (DM1) and Huntington’s disease (HD). Upon expansion, CAG/CTG repeat loci acquire heterochromatic characteristics. This observation raises the hypothesis that repeat expansion provokes changes to higher-order chromatin conformation and thereby affects both gene expression in cis and the genetic instability of the repeat tract. Here we tested this hypothesis directly by performing 4C sequencing at the DMPK and HTT loci from DM1 and HD patient-derived cells. Surprisingly, chromatin contacts remain unchanged upon repeat expansion at both loci. This was true for expanded alleles with different DNA methylation levels and CTCF binding. Repeat tract sizes ranging from 15 to 1,700 repeats displayed strikingly similar chromatin interaction profiles. Moreover, the ectopic insertion of an expanded CAG repeat tract did not change the three-dimensional chromatin conformation of the surrounding genomic region. Our findings argue that extensive changes in heterochromatic properties are not enough to alter chromatin conformation at expanded CAG/CTG repeat loci. We conclude that 3D chromatin conformation is unlikely to drive repeat expansions or changes in gene expression in expanded CAG/CTG repeat disorders. This SuperSeries is composed of the SubSeries listed below.

2020-04-07 | GSE148185 | GEO

Three-dimensional chromatin interactions remain stable upon CAG/CTG repeat expansion.

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4C-seq: Three-dimensional chromatin interactions of FMR1, HTT, DMPK, and GFP viewpoints.

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Recovery in the intrinsic myogenic program of congenital myotonic dystrophy myoblasts after excision of the expanded (CTG)n repeat

Project description:The congenital form of myotonic dystrophy type 1 (cDM) is caused by large-scale expansion of a (CTG•CAG)n repeat in DMPK and DM1-AS. Production of toxic transcripts with long trinucleotide tracts from these genes results in impediment of myogenic differentiation capacity as cDM’s most prominent morpho-phenotypic hallmark. In the current in vitro study, we compared the early differentiation programs of isogenic cDM myoblasts with and without a (CTG)2600 repeat obtained by gene editing. We found that excision of the repeat restored the ability of cDM myoblasts to engage in myogenic fusion, preventing that the ensuing myotubes remained immature. Although the cDM-typical epigenetic status of the DM1 locus and the expression of genes therein were not altered upon removal of the repeat, analyses at the transcriptome and proteome level revealed that early abnormalities in the temporal expression of differentiation regulators, myogenic progression markers and alternative splicing patterns before and immediately after the onset of differentiation became normalized. Our observation that molecular and cellular features of cDM are reversible and can be corrected by repeat-directed genome editing in muscle progenitors is important information for future development of gene therapy for different forms of DM1.

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Transcriptomic analysis of cultured isogenic myotonic dystrophy type 1 myoblasts with and without the DMPK CTG repeat

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