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Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome.
Malachowski, Thomas; Chandradoss, Keerthivasan Raanin; Boya, Ravi; Zhou, Linda; Cook, Ashley L; Su, Chuanbin; Pham, Kenneth; Haws, Spencer A; Kim, Ji Hun; Ryu, Han-Seul; Ge, Chunmin; Luppino, Jennifer M; Nguyen, Son C; Titus, Katelyn R; Gong, Wanfeng; Wallace, Owen; Joyce, Eric F; Wu, Hao; Rojas, Luis Alejandro; Phillips-Cremins, Jennifer E.
Afiliação
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Pham K; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.
  • 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.
  • Kim JH; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
  • Ryu HS; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.
  • Ge C; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
  • Luppino JM; Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.
  • Nguyen SC; Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.
  • 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.
  • 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.
  • Wallace O; Fulcrum Therapeutics Incorporated, Cambridge, MA, USA.
  • Joyce EF; Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.
  • Wu H; Fulcrum Therapeutics Incorporated, Cambridge, MA, USA.
  • Rojas LA; Fulcrum Therapeutics Incorporated, Cambridge, MA, USA.
  • 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.
Cell ; 186(26): 5840-5858.e36, 2023 12 21.
Article em En | MEDLINE | ID: mdl-38134876
ABSTRACT
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Síndrome do Cromossomo X Frágil Limite: Humans Idioma: En Revista: Cell Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Síndrome do Cromossomo X Frágil Limite: Humans Idioma: En Revista: Cell Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos