Discovery and In Vivo Characterization of Long Noncoding RNAs

Abstract

The noncoding genome, or the portion of the genome that does not encode for proteins, encompasses >95% of the human genome. It has been found that the majority of disease-associated genetic variants identified by genome-wide association studies (GWAS) are located in this noncoding 95%, where they have the potential to affect regions that control transcription (promoters, enhancers) and noncoding RNAs that also can influence gene expression. The discovery of these alterations has already contributed to a better understanding of the etiology of human diseases and has begun to yield insight into the function of these noncoding loci I am interested in studying how the noncoding genome functions and contributes to human development and disease pathology, especially when it is considered that our understanding of human disease is almost entirely contained within the realm of the <5% of the genome that is protein coding. Toward this end, I have focused my studies on one part of the noncoding genome, long noncoding RNAs. In order to identify whether long noncoding RNAs are important for mammalian development and disease, our lab created a set of lincRNA knockout animal models in which a cassette expressing beta-galactosidase (lacZ) replaces the lincRNA DNA sequence. I have used these models for the in vivo characterization of several lincRNAs, including Fendrr in the lungs, Brn1b in the brain, Tug1 in the testes, and Cox2 in the innate immune system. Each of these studies reveals perturbations in development induced by loss of function of the respective lincRNA locus, and demonstrates promising potential for further examination of the role these molecules play in human disease.