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

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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
Journal Article

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

2019
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Overview
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. The spatial organization of the genome plays an important but unclearly defined role in gene regulation. Here, the authors integrate Hi-C, RNA-seq and ATAC-seq data to map cardiogenesis from pluripotent stem cells and describe an RBM20-dependent splicing factory assembling the TTN locus with other RBM20 targets.