Genomic reorganization underlies LMNA-associated cardiomyopathies

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Science Translational Medicine  06 Mar 2019:
Vol. 11, Issue 482, eaaw7627
DOI: 10.1126/scitranslmed.aaw7627


Mutations in LMNA result in dilated cardiomyopathy through disruption of chromatin organization, methylation, and aberrant gene expression.

Mutations in LMNA result in a diverse array of phenotypes referred to as laminopathies that include dilated cardiomyopathy, Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy, lipodystrophies, and premature aging. LMNA encodes the nuclear inner membrane protein Lamin A/C that has been implicated in nuclear structural integrity, mechanotransduction, and signaling. Although the molecular mechanism(s) by which mutations in LMNA result in these diseases is unknown, it has been postulated that loss of nuclear structural integrity and dysregulated mitogen–associated protein kinase signaling may be responsible for cardiac manifestations. Recently, an alternative hypothesis has emerged implicating LMNA in the regulation of chromatin organization and gene expression. LMNA interacts with large chromatin domains referred to as Lamin-associated domains (LADs) that are distributed throughout the genome and are involved in genomic organization, epigenetic modifications, and regulation of gene expression. As many LADs are localized to heterochromatic regions enriched in repressive histone markers, genes located within LADs are generally either silenced or expressed at low levels.

By comparing cardiomyocytes from controls and patients with LMNA dilated cardiomyopathy at the epigenetic and transcriptomic level, Cheedipudi et al. demonstrated that LADs were distributed across heterochromatic, promoter, and actively transcribed regions of the genome and were associated with DNA methylation and suppressed gene expression. Intriguingly, LMNA mutations led to rearrangement of LADs at 669 loci. Within these regions, the authors observed increased DNA methylation and marked alterations in gene expression. Regions where LADs were lost displayed upregulation of gene expression, whereas regions where LADs were gained displayed repressed gene expression. Differentially expressed genes were specific to LMNA-associated dilated cardiomyopathy and involved pathways linked to mitochondrial function, catalytic activity, stress response, cell cycle regulation, extracellular organization, and MTOR signaling. Collectively, these findings identify a new potential explanation of how LMNA mutations may cause heart failure. Future studies will undoubtedly focus on the molecular mechanism by which LMNA mutations promote reorganization of LADs with the exciting possibility of identifying new therapeutic approaches for this devastating disease.

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