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J Cell Biol. 2019 Sep 2;218(9):2919-2944. doi: 10.1083/jcb.201902117. Epub 2019 Aug 8.

Chromatin compartment dynamics in a haploinsufficient model of cardiac laminopathy.

Bertero A1,2,3, Fields PA1,2,3, Smith AST2,3,4, Leonard A2,3,5, Beussman K2,3,5, Sniadecki NJ2,3,4,5, Kim DH2,3,4, Tse HF6, Pabon L1,2,3, Shendure J7,8, Noble WS7, Murry CE9,2,3,4,10.

Author information

1
Department of Pathology, University of Washington, Seattle, WA.
2
Center for Cardiovascular Biology, University of Washington, Seattle, WA.
3
Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA.
4
Department of Bioengineering, University of Washington, Seattle, WA.
5
Department of Mechanical Engineering, University of Washington, Seattle, WA.
6
Cardiology Division, Department of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong.
7
Department of Genome Sciences, University of Washington, Seattle, WA.
8
Howard Hughes Medical Institute, Seattle, WA.
9
Department of Pathology, University of Washington, Seattle, WA murry@uw.edu.
10
Department of Medicine/Cardiology, University of Washington, Seattle, WA.

Abstract

Mutations in A-type nuclear lamins cause dilated cardiomyopathy, which is postulated to result from dysregulated gene expression due to changes in chromatin organization into active and inactive compartments. To test this, we performed genome-wide chromosome conformation analyses in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with a haploinsufficient mutation for lamin A/C. Compared with gene-corrected cells, mutant hiPSC-CMs have marked electrophysiological and contractile alterations, with modest gene expression changes. While large-scale changes in chromosomal topology are evident, differences in chromatin compartmentalization are limited to a few hotspots that escape segregation to the nuclear lamina and inactivation during cardiogenesis. These regions exhibit up-regulation of multiple noncardiac genes including CACNA1A, encoding for neuronal P/Q-type calcium channels. Pharmacological inhibition of the resulting current partially mitigates the electrical alterations. However, chromatin compartment changes do not explain most gene expression alterations in mutant hiPSC-CMs. Thus, global errors in chromosomal compartmentation are not the primary pathogenic mechanism in heart failure due to lamin A/C haploinsufficiency.

PMID:
31395619
PMCID:
PMC6719452
[Available on 2020-03-02]
DOI:
10.1083/jcb.201902117

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