2. Academic Validation
  3. Dynamics of genome reorganization during human cardiogenesis reveal an RBM20-dependent splicing factory

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

  • Nat Commun. 2019 Apr 4;10(1):1538. doi: 10.1038/s41467-019-09483-5.
Alessandro Bertero 1 2 3,  Paul A Fields 1 2 3,  Vijay Ramani 4,  Giancarlo Bonora 4,  Galip G Yardimci 4,  Hans Reinecke 1 2 3,  Lil Pabon 1 2 3,  William S Noble 4,  Jay Shendure 4 5,  Charles E Murry 6 7 8 9 10
Affiliations

Affiliations

  • 1 Department of Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA.
  • 2 Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA, 98109, USA.
  • 3 Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, 98109, WA, USA.
  • 4 Department of Genome Sciences, University of Washington, William H. Foege Hall, 3720 15th Ave NE, Seattle, 98195, WA, USA.
  • 5 Howard Hughes Medical Institute, Seattle, WA, USA.
  • 6 Department of Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA. murry@uw.edu.
  • 7 Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA, 98109, USA. murry@uw.edu.
  • 8 Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, 98109, WA, USA. murry@uw.edu.
  • 9 Department of Medicine/Cardiology, 1959 NE Pacific Street, University of Washington, Seattle, 98195, WA, USA. murry@uw.edu.
  • 10 Department of Bioengineering, University of Washington, 3720 15th Ave NE, Seattle, WA, 98195, USA. murry@uw.edu.
PMID: 30948719 DOI: 10.1038/s41467-019-09483-5
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.

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