PT  - JOURNAL ARTICLE
AU  - Linda Zhou
AU  - Chunmin Ge
AU  - Thomas Malachowski
AU  - Ji Hun Kim
AU  - Keerthivasan Raanin Chandradoss
AU  - Chuanbin Su
AU  - Hao Wu
AU  - Alejandro Rojas
AU  - Owen Wallace
AU  - Katelyn R. Titus
AU  - Wanfeng Gong
AU  - Jennifer E. Phillips-Cremins
TI  - Spatially coordinated heterochromatinization of distal short tandem repeats in fragile X syndrome
AID  - 10.1101/2021.04.23.441217
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.04.23.441217
4099  - http://biorxiv.org/content/early/2021/04/24/2021.04.23.441217.short
4100  - http://biorxiv.org/content/early/2021/04/24/2021.04.23.441217.full
AB  - Short tandem repeat (STR) instability is causally linked to pathologic transcriptional silencing in a subset of repeat expansion disorders. In fragile X syndrome (FXS), instability of a single CGG STR tract is thought to repress FMR1 via local DNA methylation. Here, we report the acquisition of more than ten Megabase-sized H3K9me3 domains in FXS, including a 5-8 Megabase block around FMR1. Distal H3K9me3 domains encompass synaptic genes with STR instability, and spatially co-localize in trans concurrently with FMR1 CGG expansion and the dissolution of TADs. CRISPR engineering of mutation-length FMR1 CGG to normal-length preserves heterochromatin, whereas cut-out to pre-mutation-length attenuates a subset of H3K9me3 domains. Overexpression of a pre-mutation-length CGG de-represses both FMR1 and distal heterochromatinized genes, indicating that long-range H3K9me3-mediated silencing is exquisitely sensitive to STR length. Together, our data uncover a genome-wide surveillance mechanism by which STR tracts spatially communicate over vast distances to heterochromatinize the pathologically unstable genome in FXS.One-Sentence Summary Heterochromatinization of distal synaptic genes with repeat instability in fragile X is reversible by overexpression of a pre-mutation length CGG tract.Competing Interest StatementThe authors have declared no competing interest.