期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-019-09483-5
关键词
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资金
- EMBO Long-Term Fellowship [ALTF 448-2017]
- Experimental Pathology of Cardiovascular Disease training grant, NIH [T32 HL007312]
- Foundation Leducq Transatlantic Network of Excellence
- NIH [R24 HD000836]
- [P01 GM081619]
- [R01 HL128362]
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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