Chromatin compartment dynamics in a haploinsufficient model of cardiac laminopathy
Chromatin compartment dynamics in a haploinsufficient model of cardiac laminopathy
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DOI：
10.1083/jcb.201902117
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发表时间：
2019-09-01
影响因子：
7.8
通讯作者：
Murry, Charles E.
中科院分区：
文献类型：
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作者：
Bertero, Alessandro;Fields, Paul A.;Murry, Charles E.
A型核纤层蛋白的突变导致扩张型心肌病，这被认为是由于染色质组织变化成活性和非活性区室导致基因表达失调所致。为了验证这一点，我们在具有核纤层蛋白A/C单倍不足突变的人诱导多能干细胞衍生的心肌细胞（hiPSC-CM）中进行了全基因组染色体构象分析。与基因校正的细胞相比，突变hiPSC-CM具有显著的电生理和收缩改变，具有适度的基因表达变化。虽然染色体拓扑结构的大规模变化是显而易见的，但染色质区室化的差异仅限于几个热点，这些热点在心脏发生过程中逃脱了核纤层的分离和失活。这些区域表现出多个非心脏基因的上调，包括CACNA 1A，编码神经元P/Q型钙通道。药理学抑制所产生的电流部分缓解了电变化。然而，染色质区室的变化不能解释突变hiPSC-CM中的大多数基因表达改变。因此，染色体区室化的整体错误并不是核纤层蛋白A/C单倍不足导致心力衰竭的主要致病机制。
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.