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美国宾夕法尼亚大学Rajan Jain、Kiran Musunuru等研究人员合作发现，致病性LMNA变异体可破坏核纤层-染色质相互作用，并表达其他的命运基因。这一研究成果于2021年2月1日在线发表在国际学术期刊《细胞—干细胞》上。

研究人员表示，LAMIN A/C（LMNA）中的致病性突变会导致异常的核结构和核纤层蛋白综合征。这些疾病具有多种组织特异性表型，包括扩张型心肌病（DCM），但LMNA突变如何导致组织受限的疾病表型仍不清楚。

研究人员将DCM患者的LMNA突变引入人类诱导型多能干细胞（hiPSC）中，并发现与肝细胞或脂肪细胞相比，hiPSC衍生的心肌细胞显示出异常的核形态和外周染色质的特异性破坏。破坏区域富含转录活跃基因和较低LAMIN B1接触频率的区域。在突变型心肌细胞中破坏的层状染色质相互作用富集了与非肌细胞谱系相关的基因，并与这些基因的更高表达相关。

来自具有LMNA变体患者的心肌类似地显示出非心肌细胞途径的异常表达。研究人员认为，核纤层网络可保护细胞身份，而致病性LMNA变异体可破坏具有特定表观遗传学和分子特征的外周染色质，从而导致通常在其他细胞类型中表达基因的错误表达。 

附：英文原文

Title: Pathogenic LMNA variants disrupt cardiac lamina-chromatin interactions and de-repress alternative fate genes

Author: Parisha P. Shah, Wenjian Lv, Joshua H. Rhoades, Andrey Poleshko, Deepti Abbey, Matthew A. Caporizzo, Ricardo Linares-Saldana, Julie G. Heffler, Nazish Sayed, Dilip Thomas, Qiaohong Wang, Liam J. Stanton, Kenneth Bedi, Michael P. Morley, Thomas P. Cappola, Anjali T. Owens, Kenneth B. Margulies, David B. Frank, Joseph C. Wu, Daniel J. Rader, Wenli Yang, Benjamin L. Prosser, Kiran Musunuru, Rajan Jain

Issue&Volume: 2021-02-01

Abstract: Pathogenic mutations in LAMIN A/C (LMNA) cause abnormal nuclear structure and laminopathies.These diseases have myriad tissue-specific phenotypes, including dilated cardiomyopathy(DCM), but how LMNA mutations result in tissue-restricted disease phenotypes remainsunclear. We introduced LMNA mutations from individuals with DCM into human inducedpluripotent stem cells (hiPSCs) and found that hiPSC-derived cardiomyocytes, in contrastto hepatocytes or adipocytes, exhibit aberrant nuclear morphology and specific disruptionsin peripheral chromatin. Disrupted regions were enriched for transcriptionally activegenes and regions with lower LAMIN B1 contact frequency. The lamina-chromatin interactionsdisrupted in mutant cardiomyocytes were enriched for genes associated with non-myocytelineages and correlated with higher expression of those genes. Myocardium from individualswith LMNA variants similarly showed aberrant expression of non-myocyte pathways. We proposethat 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.

DOI: 10.1016/j.stem.2020.12.016

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30600-7

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