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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Cell Differentiation / genetics*
  • Gene Expression Regulation, Developmental
  • Gene Regulatory Networks
  • Heart / growth & development
  • Humans
  • Myocardium / cytology
  • Myocardium / metabolism
  • Organogenesis / genetics
  • Pluripotent Stem Cells
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • RNA-Binding Proteins / physiology*

Substances

  • RNA-Binding Proteins
  • ribonucleic acid binding motif protein 20, human