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
  • 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. [email protected].
  • 7. Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA, 98109, USA. [email protected].
  • 8. Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, 98109, WA, USA. [email protected].
  • 9. Department of Medicine/Cardiology, 1959 NE Pacific Street, University of Washington, Seattle, 98195, WA, USA. [email protected].
  • 10. Department of Bioengineering, University of Washington, 3720 15th Ave NE, Seattle, WA, 98195, USA. [email protected].
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.