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Spatially coordinated heterochromatinization of distal short tandem repeats in fragile X syndrome

Linda Zhou, Chunmin Ge, Thomas Malachowski, Ji Hun Kim, Keerthivasan Raanin Chandradoss, Chuanbin Su, Hao Wu, Alejandro Rojas, Owen Wallace, Katelyn R. Titus, Wanfeng Gong, View ORCID ProfileJennifer E. Phillips-Cremins
doi: https://doi.org/10.1101/2021.04.23.441217
Linda Zhou
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
3Department of Genetics, Perelman School of Medicine, University of Pennsylvania
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Chunmin Ge
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
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Thomas Malachowski
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
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Ji Hun Kim
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
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Keerthivasan Raanin Chandradoss
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
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Chuanbin Su
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
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Hao Wu
5Fulcrum Therapeutics Incorporated, Cambridge, MA
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Alejandro Rojas
5Fulcrum Therapeutics Incorporated, Cambridge, MA
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Owen Wallace
5Fulcrum Therapeutics Incorporated, Cambridge, MA
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Katelyn R. Titus
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
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Wanfeng Gong
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
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Jennifer E. Phillips-Cremins
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
2Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania
3Department of Genetics, Perelman School of Medicine, University of Pennsylvania
4New York Stem Cell Foundation – Robertson Investigator
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  • ORCID record for Jennifer E. Phillips-Cremins
  • For correspondence: jcremins@seas.upenn.edu
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Abstract

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 Statement

The authors have declared no competing interest.

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Posted April 24, 2021.
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Spatially coordinated heterochromatinization of distal short tandem repeats in fragile X syndrome
Linda Zhou, Chunmin Ge, Thomas Malachowski, Ji Hun Kim, Keerthivasan Raanin Chandradoss, Chuanbin Su, Hao Wu, Alejandro Rojas, Owen Wallace, Katelyn R. Titus, Wanfeng Gong, Jennifer E. Phillips-Cremins
bioRxiv 2021.04.23.441217; doi: https://doi.org/10.1101/2021.04.23.441217
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Spatially coordinated heterochromatinization of distal short tandem repeats in fragile X syndrome
Linda Zhou, Chunmin Ge, Thomas Malachowski, Ji Hun Kim, Keerthivasan Raanin Chandradoss, Chuanbin Su, Hao Wu, Alejandro Rojas, Owen Wallace, Katelyn R. Titus, Wanfeng Gong, Jennifer E. Phillips-Cremins
bioRxiv 2021.04.23.441217; doi: https://doi.org/10.1101/2021.04.23.441217

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