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Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome [Nanopore]

ABSTRACT: Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome [Nanopore]

PROVIDER: PRJNA904800 | ENA |

REPOSITORIES: ENA

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Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome

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Project description:Short tandem repeat (STR) instability causes transcriptional silencing in several repeat expansion disorders. In fragile X syndrome (FXS), mutation-length expansion of a CGG STR represses FMR1 via local DNA methylation. Here, we find Megabase-scale H3K9me3 domains on autosomes and encompassing FMR1 on the X-chromosome in induced pluripotent stem cell (iPSC)-derived neural progenitors, B-cells, and fibroblasts with mutation-length CGG expansion. H3K9me3 domains connect via inter-chromosomal interactions and demarcate severe misfolding of TADs and loops. They harbor long synaptic genes replicating at the end of S phase, replication stress-induced double strand breaks, and STRs prone to stepwise somatic instability. CRISPR engineering of the full-mutation CGG to premutation-length reverses H3K9me3 domains on the X-chromosome and multiple autosomes, refolds TADs, and restores expression. H3K9me3 domains also arise in a subset of normal-length iPSCs with increased STR instability burden. Our results reveal Mb-scale heterochromatinization and trans interactions among chromosomes susceptible to repeat genetic instability.

2023-12-21 | GSE218679 | GEO

Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome [WGS]

2023-12-21 | GSE218678 | GEO

Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome [CUT&RUN]

2023-12-21 | GSE218677 | GEO

Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome [Hi-C]

2023-12-21 | GSE218675 | GEO