Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome

• DOI: 10.1016/j.cell.2023.11.019
• Publication Date: 2023-12-21T15:35:49Z
• Authors: Thomas Malachowski; Keerthivasan Raan...; Ravi Boya; Linda Zhou; Ashley L. Cook; Chuanbin Su; Kenneth Pham; Spencer A. Haws; Ji Hun Kim; Han-Seul Ryu; Chunmin Ge; Jennifer M. Luppino; Son C. Nguyen; Katelyn R. Titus; Wanfeng Gong; Owen Wallace; Eric F. Joyce; Hao Wu; Luis Alejandro Rojas; Jennifer E. Phill...
• Keywords: FMR1; Haploinsufficiency; Fragile X Syndrome; Chromosomal fragile site; Chromosome instability

Short tandem repeat (STR) instability causes transcriptional silencing in several expansion disorders. In fragile X syndrome (FXS), mutation-length of a CGG STR represses FMR1 via local DNA methylation. Here, we find megabase-scale H3K9me3 domains on autosomes and encompassing the chromosome FXS patient-derived iPSCs, iPSC-derived neural progenitors, EBV-transformed lymphoblasts, brain tissue with expansion. connect inter-chromosomal interactions demarcate severe misfolding TADs loops. They harbor long synaptic genes replicating at end S phase, replication-stress-induced double-strand breaks, STRs prone to stepwise somatic instability. CRISPR engineering premutation length reverses multiple autosomes, refolds TADs, restores gene expression. can also arise normal-length iPSCs created perturbations linked genome instability, suggesting their relevance beyond FXS. Our results reveal Mb-scale heterochromatinization trans among loci susceptible