Pathogenic LMNA variants disrupt cardiac lamina-chromatin interactions and de-repress alternative fate genes.
Pathogenic LMNA variants disrupt cardiac lamina-chromatin interactions and de-repress alternative fate genes.
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DOI：
10.1016/j.stem.2020.12.016
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发表时间：
2021-05-06
期刊：
影响因子：
23.9
通讯作者：
Jain R
中科院分区：
文献类型：
--
作者：
Shah PP;Lv W;Rhoades JH;Poleshko A;Abbey D;Caporizzo MA;Linares-Saldana R;Heffler JG;Sayed N;Thomas D;Wang Q;Stanton LJ;Bedi K;Morley MP;Cappola TP;Owens AT;Margulies KB;Frank DB;Wu JC;Rader DJ;Yang W;Prosser BL;Musunuru K;Jain R
LMNA的致病突变会导致核结构异常和椎板病变。这些疾病有无数的组织特异性表型，包括扩张型心肌病(DCM)，尽管LMNA突变如何导致组织限制性疾病表型尚不清楚。我们将DCM患者LMNA突变引入HiPSC，发现与肝细胞或脂肪细胞相比，HiPSC来源的心肌细胞表现出异常的核形态和外周染色质的特异性破坏。被破坏的区域富含转录活性基因和Lamin B1接触频率较低的区域。突变心肌细胞的膜-染色质相互作用被破坏，与非心肌细胞谱系相关的基因丰富，并与这些基因的高表达相关。LMNA变异型患者的心肌同样表现出非心肌细胞途径的异常表达。我们认为，板层网络保护细胞身份，致病的LMNA变体破坏具有特定表观遗传学和分子特征的外周染色质，导致在其他类型细胞中正常表达的基因的错误表达。Jain、Musunuru和他的同事证明了致病的LMNA变体以一种细胞类型特定的方式影响外周染色质组织。他们的数据表明，板层和染色质的相互作用保护着细胞的身份。致病的LMNA变异体扰乱外周染色质组织，并取消心肌细胞中可选命运基因的正常沉默。
Pathogenic mutations in LMNA cause abnormal nuclear structure and laminopathies. These diseases have myriad tissue-specific phenotypes including dilated cardiomyopathy (DCM), although how LMNA mutations result in tissue-restricted disease phenotypes remains unclear. We introduced DCM patient LMNA mutations into hiPSCs and found that hiPSC-derived cardiomyocytes, in contrast to hepatocytes or adipocytes, exhibit aberrant nuclear morphology and specific disruptions in peripheral chromatin. Disrupted regions were enriched for transcriptionally active genes and regions with lower LAMIN B1 contact frequency. The lamina-chromatin interactions disrupted in mutant cardiomyocytes were enriched for genes associated with non-myocyte lineages and correlated with higher expression of those genes. Myocardium from patients with LMNA variants similarly showed aberrant expression of non-myocyte pathways. We propose that the lamina network safeguards cellular identity and that pathogenic LMNA variants disrupt peripheral chromatin with specific epigenetic and molecular characteristics, causing misexpression of genes normally expressed in other cell types. Jain, Musunuru and colleagues demonstrate pathogenic LMNA variants affect peripheral chromatin organization in a cell-type specific manner. Their data suggest that lamina-chromatin interactions guard cellular identity. Pathogenic LMNA variants disrupt peripheral chromatin organization and abrogate normal silencing of alternative fate genes in cardiomyocytes.
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