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Autor(en): Albrecht, Claudia
Rajaram, Nivethika
Broche, Julian
Bashtrykov, Pavel
Jeltsch, Albert
Titel: Locus-specific and stable DNA demethylation at the H19/IGF2 ICR1 by epigenome editing using a dCas9-SunTag system and the catalytic domain of TET1
Erscheinungsdatum: 2024
Dokumentart: Zeitschriftenartikel
Seiten: 15
Erschienen in: Genes 15 (2024), No. 80
URI: http://nbn-resolving.de/urn:nbn:de:bsz:93-opus-ds-143678
http://elib.uni-stuttgart.de/handle/11682/14367
http://dx.doi.org/10.18419/opus-14348
ISSN: 2073-4425
Zusammenfassung: DNA methylation is critically involved in the regulation of chromatin states and cell-type-specific gene expression. The exclusive expression of imprinted genes from either the maternal or the paternal allele is regulated by allele-specific DNA methylation at imprinting control regions (ICRs). Aberrant DNA hyper- or hypomethylation at the ICR1 of the H19/IGF2 imprinting locus is characteristic for the imprinting disorders Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS), respectively. In this paper, we performed epigenome editing to induce targeted DNA demethylation at ICR1 in HEK293 cells using dCas9-SunTag and the catalytic domain of TET1. 5-methylcytosine (5mC) levels at the target locus were reduced up to 90% and, 27 days after transient transfection, >60% demethylation was still observed. Consistent with the stable demethylation of CTCF-binding sites within the ICR1, the occupancy of the DNA methylation-sensitive insulator CTCF protein increased by >2-fold throughout the 27 days. Additionally, the H19 expression was increased by 2-fold stably, while IGF2 was repressed though only transiently. Our data illustrate the ability of epigenome editing to implement long-term changes in DNA methylation at imprinting control regions after a single transient treatment, potentially paving the way for therapeutic epigenome editing approaches in the treatment of imprinting disorders.
Enthalten in den Sammlungen:03 Fakultät Chemie

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