TY - JOUR
T1 - Identification of genes and pathways regulated by lamin a in heart
AU - Pradas, Jordi Coste
AU - Auguste, Gaelle
AU - Matkovich, Scot J.
AU - Lombardi, Raffaella
AU - Chen, Suet Nee
AU - Garnett, Tyrone
AU - Chamberlain, Kyle
AU - Riyad, Jalish Mahmud
AU - Weber, Thomas
AU - Singh, Sanjay K.
AU - Robertson, Matthew J.
AU - Coarfa, Cristian
AU - Marian, Ali J.
AU - Gurha, Priyatansh
N1 - Publisher Copyright:
© 2020 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
PY - 2020/8/16
Y1 - 2020/8/16
N2 - BACKGROUND: Mutations in the LMNA gene, encoding LMNA (lamin A/C), causes distinct disorders, including dilated cardiomyopathies, collectively referred to as laminopathies. The genes (coding and noncoding) and regulatory pathways controlled by LMNA in the heart are not completely defined. METHODS AND RESULTS: We analyzed cardiac transcriptome from wild-type, loss-of-function (Lmna−/−), and gain-of-function (Lmna−/− injected with adeno-associated virus serotype 9 expressing LMNA) mice with normal cardiac function. Deletion of Lmna (Lmna−/−) led to differential expression of 2193 coding and 629 long noncoding RNA genes in the heart (q<0.05). Reexpression of LMNA in the Lmna−/− mouse heart, completely rescued 501 coding and 208 non-coding and partially rescued 1862 coding and 607 lncRNA genes. Pathway analysis of differentially expressed genes predicted activation of transcriptional regulators lysine-specific demethylase 5A, lysine-specific demethylase 5B, tumor protein 53, and suppression of ret-inoblastoma 1, paired-like homeodomain 2, and melanocyte-inducing transcription factor, which were completely or partially rescued upon reexpression of LMNA. Furthermore, lysine-specific demethylase 5A and 5B protein levels were increased in the Lmna−/− hearts and were partially rescued upon LMNA reexpression. Analysis of biological function for rescued genes identified activation of tumor necrosis factor-α, epithelial to mesenchymal transition, and suppression of the oxidative phosphorylation pathway upon Lmna deletion and their restoration upon LMNA reintroduction in the heart. Restoration of the gene expression and transcriptional regulators in the heart was associated with improved cardiac function and increased survival of the Lmna−/− mice. CONCLUSIONS: The findings identify LMNA-regulated cardiac genes and their upstream transcriptional regulators in the heart and implicate lysine-specific demethylase 5A and B as epigenetic regulators of a subset of the dysregulated genes in laminopathies.
AB - BACKGROUND: Mutations in the LMNA gene, encoding LMNA (lamin A/C), causes distinct disorders, including dilated cardiomyopathies, collectively referred to as laminopathies. The genes (coding and noncoding) and regulatory pathways controlled by LMNA in the heart are not completely defined. METHODS AND RESULTS: We analyzed cardiac transcriptome from wild-type, loss-of-function (Lmna−/−), and gain-of-function (Lmna−/− injected with adeno-associated virus serotype 9 expressing LMNA) mice with normal cardiac function. Deletion of Lmna (Lmna−/−) led to differential expression of 2193 coding and 629 long noncoding RNA genes in the heart (q<0.05). Reexpression of LMNA in the Lmna−/− mouse heart, completely rescued 501 coding and 208 non-coding and partially rescued 1862 coding and 607 lncRNA genes. Pathway analysis of differentially expressed genes predicted activation of transcriptional regulators lysine-specific demethylase 5A, lysine-specific demethylase 5B, tumor protein 53, and suppression of ret-inoblastoma 1, paired-like homeodomain 2, and melanocyte-inducing transcription factor, which were completely or partially rescued upon reexpression of LMNA. Furthermore, lysine-specific demethylase 5A and 5B protein levels were increased in the Lmna−/− hearts and were partially rescued upon LMNA reexpression. Analysis of biological function for rescued genes identified activation of tumor necrosis factor-α, epithelial to mesenchymal transition, and suppression of the oxidative phosphorylation pathway upon Lmna deletion and their restoration upon LMNA reintroduction in the heart. Restoration of the gene expression and transcriptional regulators in the heart was associated with improved cardiac function and increased survival of the Lmna−/− mice. CONCLUSIONS: The findings identify LMNA-regulated cardiac genes and their upstream transcriptional regulators in the heart and implicate lysine-specific demethylase 5A and B as epigenetic regulators of a subset of the dysregulated genes in laminopathies.
KW - Cardiomyopathies
KW - KDM5
KW - LMNA
KW - Laminopathies
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U2 - 10.1161/JAHA.119.015690
DO - 10.1161/JAHA.119.015690
M3 - Article
C2 - 32805188
AN - SCOPUS:85089556192
SN - 2047-9980
VL - 9
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 16
M1 - e015690
ER -