Challenging the "chromatin hypothesis" of cardiac laminopathies with LMNA mutant iPS cells

Abstract

Lamins A and C are intermediate filaments that provide structural support to the nuclear envelope and regulate gene expression. In this issue, Bertero et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201902117) report that although lamin A/C haploinsufficient cardiomyocytes show disease-associated phenotypes, those changes cannot be explained by alterations in chromatin compartmentalization.

Figure 1.

Chromatin compartmentalization dynamics in healthy control (or corrected by gene editing) and LMNA haploinsufficient CMs derived from hiPSC-CMs. The cartoon depicts the key stages of directed differentiation of hiPSCs to CMs. On the right-hand side, two CMs are magnified and their respective WT (top) and LMNA mutant (bottom) nuclei are shown. Nuclear compartmentalization in A (orange) and B (gray) domains are represented, as well as lamin A/C distribution as a red circle (solid in WT and dashed in mutant nuclei), underneath the nuclear membrane (black circle). Chromosome territories (depicted as tangled colored lines) are shown more separated in LMNA-R225X hiPSC-CMs as compared with WT/corrected cells, and the consequent dysregulation of the CACCNA1 gene, which moves from the periphery (WT) to the nuclear interior (R225X LMNA), is highlighted. Illustration produced using SMART (Servier Medical Art; https://smart.servier.com) in accordance with a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/).