Author + information
- Zaicheng Xu and
- Chunyu Zeng
Previous studies have shown that long non-coding RNA (lncRNA) played a key role in many processes, and can functioning as scaffolds that regulate protein-protein, protein- RNA or RNA -RNA interactions, however, it's role in cardiac hypertrophy poorly understood.
A microarray was performed to analyze mice heart LncRNAs and mRNAs in response to sham surgery or transverse aortic constriction (TAC) 1 week or 2 weeks to induce pressure overload. Then we validate candidate lncRNAs by real-time PCR, and study the function by shRNA to knock down ANP-AS expression. Genome-wide analysis was taked after knocking down ANP-AS. RNA-protein interaction and protein -protein interaction was tested by RNA immunoprecipitation (RIP) and Co-IP.
We found a heart-specific lncRNA, who is conserved among species and located in the the antisense strand of coding gene ANP, thus we named it lncRNA ANP-AS (ANP-antisense). ANP-AS plays a key regulatory role in cardiac hypertrophy, it's expression level in human failure heart or mice hypertrophy heart is much higher than normal, through loss-of-function approaches, we showed that shANP-AS will significantly protect heart from hypertrophy. Genome-wide analysis revealed that changes of ANP-AS expression have the most obvious effect on hypertrophy, cardiac metabolism, cell cycle signaling pathways. P300/CBP expression will increase when cardiac hypertrophy, and then bind to transcripttion factors GATA4 and MEF2, thus induce their acetylation to increase transcription of fetel genes and promote cardiac hypertrophy. We found this acetylation process of p300/CBP is mediated by ANP-AS: ANP-AS can bind not only p300/CBP but also GATA4, MEF2 at different positions act as a molecular scaffold, lead them to bind together and promote GATA4, MEF2 acetylation, then regulates cardiac hypertrophy. Once knocke down ANP-AS expression, acetylation of GATA4, MEF2 will be inhibited, thus significantly alleviate cardiac hypertrophy.
Our study found a new causative cardiac hypertrophy transcript, define a new mechanism for p300/CBP acetylation process when cardiac hypertrophy, and provide a potential therapeutic target.