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

Alessandro Bertero, Paul A. Fields, Vijay Ramani, Giancarlo Bonora, Galip G. Yardimci, Hans Reinecke, Lil Pabon, William S. Noble, Jay Shendure and Charles E. Murry ()
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Alessandro Bertero: University of Washington
Paul A. Fields: University of Washington
Vijay Ramani: University of Washington
Giancarlo Bonora: University of Washington
Galip G. Yardimci: University of Washington
Hans Reinecke: University of Washington
Lil Pabon: University of Washington
William S. Noble: University of Washington
Jay Shendure: University of Washington
Charles E. Murry: University of Washington

Nature Communications, 2019, vol. 10, issue 1, 1-19

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09483-5

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