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Dynamics of genome reorganization during human cardiogenesis reveal an RBM20-dependent splicing factory

Author

Listed:
  • Alessandro Bertero

    (University of Washington
    University of Washington
    University of Washington)

  • Paul A. Fields

    (University of Washington
    University of Washington
    University of Washington)

  • Vijay Ramani

    (University of Washington)

  • Giancarlo Bonora

    (University of Washington)

  • Galip G. Yardimci

    (University of Washington)

  • Hans Reinecke

    (University of Washington
    University of Washington
    University of Washington)

  • Lil Pabon

    (University of Washington
    University of Washington
    University of Washington)

  • William S. Noble

    (University of Washington)

  • Jay Shendure

    (University of Washington
    Howard Hughes Medical Institute)

  • Charles E. Murry

    (University of Washington
    University of Washington
    University of Washington
    Department of Medicine/Cardiology)

Abstract

Functional changes in spatial genome organization during human development are poorly understood. Here we report a comprehensive profile of nuclear dynamics during human cardiogenesis from pluripotent stem cells by integrating Hi-C, RNA-seq and ATAC-seq. While chromatin accessibility and gene expression show complex on/off dynamics, large-scale genome architecture changes are mostly unidirectional. Many large cardiac genes transition from a repressive to an active compartment during differentiation, coincident with upregulation. We identify a network of such gene loci that increase their association inter-chromosomally, and are targets of the muscle-specific splicing factor RBM20. Genome editing studies show that TTN pre-mRNA, the main RBM20-regulated transcript in the heart, nucleates RBM20 foci that drive spatial proximity between the TTN locus and other inter-chromosomal RBM20 targets such as CACNA1C and CAMK2D. This mechanism promotes RBM20-dependent alternative splicing of the resulting transcripts, indicating the existence of a cardiac-specific trans-interacting chromatin domain (TID) functioning as a splicing factory.

Suggested Citation

  • Alessandro Bertero & Paul A. Fields & Vijay Ramani & Giancarlo Bonora & Galip G. Yardimci & Hans Reinecke & Lil Pabon & William S. Noble & Jay Shendure & Charles E. Murry, 2019. "Dynamics of genome reorganization during human cardiogenesis reveal an RBM20-dependent splicing factory," Nature Communications, Nature, vol. 10(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09483-5
    DOI: 10.1038/s41467-019-09483-5
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    Cited by:

    1. Aidan M. Fenix & Yuichiro Miyaoka & Alessandro Bertero & Steven M. Blue & Matthew J. Spindler & Kenneth K. B. Tan & Juan A. Perez-Bermejo & Amanda H. Chan & Steven J. Mayerl & Trieu D. Nguyen & Caitli, 2021. "Gain-of-function cardiomyopathic mutations in RBM20 rewire splicing regulation and re-distribute ribonucleoprotein granules within processing bodies," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. Hye Ji Cha & Özgün Uyan & Yan Kai & Tianxin Liu & Qian Zhu & Zuzana Tothova & Giovanni A. Botten & Jian Xu & Guo-Cheng Yuan & Job Dekker & Stuart H. Orkin, 2021. "Inner nuclear protein Matrin-3 coordinates cell differentiation by stabilizing chromatin architecture," Nature Communications, Nature, vol. 12(1), pages 1-19, December.

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