@article{1c49428e61db4782ab5a15b85c98bc60,
title = "Dynamics of genome reorganization during human cardiogenesis reveal an RBM20-dependent splicing factory",
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.",
author = "Alessandro Bertero and Fields, {Paul A.} and Vijay Ramani and Giancarlo Bonora and Yardimci, {Galip G.} and Hans Reinecke and Lil Pabon and Noble, {William S.} and Jay Shendure and Murry, {Charles E.}",
note = "Funding Information: Thank you to members of the Murry lab for helpful discussions during the development of this project and especially to Xiulan Yang for assistance with obtaining samples and Katie Mitzelfelt and Silvia Marchian{\`o} for experimental support. We thank members of the Shendure and Noble labs and in particular Ruolan Qiu and Kate Cook for assistance with Hi-C technology and analysis. Flow cytometry was done with assistance from UW Cell Analysis Facility in the Department of Immunology. We would like to acknowledge the Mike and Lynn Garvey Cell Imaging Lab at UW and its director Dale Hailey for assistance with sample imaging and analysis. We thank members of the Birth Defects Research Laboratory for assistance in obtaining human heart tissue. A.B. is funded by an EMBO Long-Term Fellowship, ALTF 448-2017. P.A.F. is funded through Experimental Pathology of Cardiovascular Disease training grant, NIH T32 HL007312. This work is part of the NIH 4D Nucleome consortium (NIH U54 DK107979, to C.E.M., W.S.N. and J.S.), with additional support from P01 GM081619, R01 HL128362, and the Foundation Leducq Transatlantic Network of Excellence (to C.E.M.). The Birth Defects Research Laboratory is supported by NIH grant R24 HD000836. Publisher Copyright: {\textcopyright} 2019, The Author(s).",
year = "2019",
month = dec,
day = "1",
doi = "10.1038/s41467-019-09483-5",
language = "English (US)",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}