GSE218679 Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome [Nanopore]

Contributors : Thomas Malachowski ; Keerthivasan R Chandradoss ; Linda Zhou ; Ravi Boya ; Ashley Cook ; Jennifer E Phillips-CreminsSeries Type : OtherOrganism : Homo sapiensShort 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-l ength 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 chr omosomes susceptible to repeat genetic instability.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Other Homo sapiens Source Type: research