Dynamics of genome reorganization during human cardiogenesis reveal an RBM20-dependent splicing factory
Summary
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.
| Authors | Bertero A, Fields PA, Ramani V, Bonora G, Yardimci GG, Reinecke H, Pabon L, Noble WS, Shendure J, Murry CE |
|---|---|
| Journal | Nature communications |
| Publication Date | 2019 Apr 4;10(1):1538 |
| PubMed | 30948719 |
| PubMed Central | PMC6449405 |
| DOI | 10.1038/s41467-019-09483-5 |