GSE135288
Lamin A/C regulates lncRNAs and epigenetic network in the heart
Mutations in Lamin A/C (LMNA) cause a heterogeneous group of genetic disorders named as laminopathies. LMNA, an inner nuclear membrane protein, is implicated in nuclear genome organization and gene expression. Our objectives were to identify and define the coding and noncoding gene regulatory networks that are controlled by LMNA in the heart. Sequencing of cardiac transcripts from 2-week old wild-type (WT, N=9) and Lmna-/- (N=8) mice showed differential expression of 2,193 protein coding  (817 up/1,222 down) and  629 long non-coding RNAs (lncRNAs) (193 up/436 down,) in Lmna-/- as compared to WT hearts. AAV9 mediated re-introduction of WT LMNA in the Lmna-/- mouse heart was associated with expression changes of (normalization towards WT) of transcript levels of 1,862 coding genes and 607 lncRNAs. Of these 500 coding and 208 lncRNAs showed complete rescue in expression upon LMNA reintroduction. Restoration of the transcript levels was associated with improved heart function and increased survival. Analysis of rescued genes identified histone H3K4 demethylases KDM5A and KDM5B, among the most activated transcriptional regulators.   GO analysis for KDM5A targets showed enrichment of genes involved in mitochondrial function and oxidative phosphorylation whereas KDM5B targets were enriched for those involved in cell proliferation and differentiation.  Furthermore, based on the publicly available KDM5A ChIP-seq, 124 differentially expressed lncRNAs were identified as putative targets of KDM5A. Consistent with these findings KDM5A and 5B protein levels is increased in nuclear extracts from Lmna-/- heart and are partially rescued upon AAV9 treatment. Thus, the findings implicate dysregulation of KDM5 and its downstream regulatory network involved in the pathogenesis of laminopathies. Overall design: RNA-seq from Lmna-/- and AAV9 treated Lmna-/- mice heart