Exploring the function of NkxUS, a novel heart-associated lncRNA

Altekoester A1,3, Schonrock N2, Wu J1, Kesteven S1 and Harvey RP1

  1. Victor Chang Cardiac Research Institute, Australia.
  2. Garvan Institute of Medical Research, Australia.
  3. University of Cologne, Germany.

A significant large amount of the mammalian genome previously found to not code for proteins and considered "junk", was found to actually specify a dynamic network of regulatory RNAs, termed long non-coding RNAs (lncRNAs). Here, we identified Nkx2-5UPSTREAM (NkxUS), a heart-associated lncRNA, which lies upstream of the cardiac key transcriptional regulator NKX2-5. In humans, NKX2-5 is essential for proper heart development and mutations are commonly associated with congenital heart disease. We hypothesise that NkxUS either regulates NKX2-5 itself or other processes affecting heart function and development. The aim of my study is to fully characterize NkxUS especially its function. Our studies show that NkxUS is a long, cardiac and nuclear enriched transcript. It is expressed in the heart throughout development and a similar heart specific transcript occurs in humans. We found a heart rate-associated GWAS SNP, located within human NkxUS, which lies within and disrupts a RNA structure conserved between mouse and human. When knocking down the mature transcript, genes involved in heart contraction and calcium signalling are down regulated. Mice lacking the conserved structure exhibit a higher resting heart rate with no differences in ECG parameter intervals, suggesting a possible dysfunction in the sinoatrial node (SAN), the pacemaker of the heart. Currently, we are performing calcium and voltage imaging combined with drug treatments on dissected mouse SANs to identify the basis of the phenotype. Further, we are testing the inducibility of atrial fibrillation (AF) in the same mice as the SNP was also associated with a higher risk of developing AF. Altogether, we present data on a novel cardiac enriched lncRNA and provide a detailed characterisation of this transcript to analyse how it might impact heart function and disease.