Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome.

CRISPR DNA FISH Hi-C chromatin epigenetics fragile X syndrome heterochromatin higher-order genome folding repeat expansion disorders short tandem repeats topologically associating domains

Journal

Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066

Informations de publication

Date de publication:
21 Dec 2023
Historique:
received: 03 12 2022
revised: 31 07 2023
accepted: 16 11 2023
medline: 23 12 2023
pubmed: 23 12 2023
entrez: 22 12 2023
Statut: ppublish

Résumé

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 FXS patient-derived iPSCs, iPSC-derived neural progenitors, EBV-transformed lymphoblasts, and brain tissue 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 mutation-length CGG to premutation length reverses H3K9me3 on the X chromosome and multiple autosomes, refolds TADs, and restores gene expression. H3K9me3 domains can also arise in normal-length iPSCs created with perturbations linked to genome instability, suggesting their relevance beyond FXS. Our results reveal Mb-scale heterochromatinization and trans interactions among loci susceptible to instability.

Identifiants

DOI: 10.1016/j.cell.2023.11.019 PMID: 38134876
pubmed: 38134876
pii: S0092-8674(23)01273-4
doi: 10.1016/j.cell.2023.11.019
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

5840-5858.e36

Informations de copyright

Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests L.Z., C.G., and J.E.P.-C. are inventors on patent US20220323553A1 related to this work (https://patents.google.com/patent/US20220323553A1/en).

Auteurs

Thomas Malachowski (T)

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.

Keerthivasan Raanin Chandradoss (KR)

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.

Ravi Boya (R)

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.

Linda Zhou (L)

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.

Ashley L Cook (AL)

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.

Chuanbin Su (C)

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.

Kenneth Pham (K)

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.

Spencer A Haws (SA)

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.

Ji Hun Kim (JH)

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.

Han-Seul Ryu (HS)

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.

Chunmin Ge (C)

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.

Jennifer M Luppino (JM)

Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.

Son C Nguyen (SC)

Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.

Katelyn R Titus (KR)

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.

Wanfeng Gong (W)

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.

Owen Wallace (O)

Fulcrum Therapeutics Incorporated, Cambridge, MA, USA.

Eric F Joyce (EF)

Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.

Hao Wu (H)

Fulcrum Therapeutics Incorporated, Cambridge, MA, USA.

Luis Alejandro Rojas (LA)

Fulcrum Therapeutics Incorporated, Cambridge, MA, USA.

Jennifer E Phillips-Cremins (JE)

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: jcremins@seas.upenn.edu.

Classifications MeSH