부산대학교 도서관

Introduction: Mutations in Lamin A/C (LMNA) are major causes of dilated cardiomyopathy (DCM). LMNA an inner nuclear membrane protein is considered to be essential for nuclear genome organization and gene expression. However, the role of LMNA in regulation of gene expression in the heart and particularly in DCM is unknown.Objectives: To identify and define the gene regulatory networks governed by LMNA in the heart.Results: RNA sequencing was performed in 2-week old LMNA-deficient (Lmna) and wild type (WT) littermates, prior to cardiac dysfunction. 2088 genes (929 up /1159 down at FDR 5%) were dysregulated in Lmna as compared to WT hearts. Bioinformatics analysis identified Histone H3K4 demethylases KDM5A and KDM5B, transcription factor/coactivators Nuclear protein 1(NUPR1), Forkhead box protein (FOXO4), and Tripartite Motif Containing 24 (TRIM24) among the activated transcriptional regulators in the Lmna mouse hearts. Whereas, Retinoblastoma1 (RB1) and E2F targets were suppressed. Pathway analysis identified enrichment of genes involved in cell death, cell cycle and senescence in Lmna hearts. Activation of KDM5A in Lmna hearts was associated with suppression of genes involved in oxidative phosphorylation, TCA cycle and mitochondrial function, suggesting a role of LMNA in maintenance of cardiac energy homeostasis. The phenotypic consequences of these transcriptional changes manifested at 4-weeks of age as increased apoptosis, mitochondrial dysfunction and heart failure. To further determine the effects of LMNA deficiency on gene expression, Lmna mice were injected with AAV9 expressing full-length WT LMNA (LmnaAAV9-Lmna). Over-expression of LMNA rescued epigenetic (KDM5A and B) and transcription factor networks (FOXO4 and TRIM24), indicating its prominent regulatory role. Concordant with the molecular rescue, overexpression of the LMNA in the Lmna was associated with decreased apoptosis, improved heart function and increased survival.Conclusions: LMNA regulates expression of a large number of genes and regulatory networks in the heart involved in energy metabolism, cell cycle progression, and apoptosis. The findings identify KDM5A as an attractive therapeutic target in DCM in LMNA deficiency.