Connecting non-coding variants in lncRNA loci to target genes
Only about two percent of the human genome are protein-coding, while the rest divides in transcribed to non-coding RNA or comprises or untranscribed intergenic regions. Both, ncRNAs (such as lncRNAs) and regulatory DNA elements (such as enhancers) help to determine when and where genes are turned ON or OFF. This process of transcriptional regulation appears to be essential for a variety of human diseases, since most disease variants lie in lncRNA loci and may act via effects on gene regulation. However, for most lncRNAs, the affected target genes and mechanisms of action are unknown. The Andergassen lab aims to connect variants to heart function by systematically linking CVDs-variants in lncRNA loci to their target genes, taking advantage of the allele-specific information (Andergassen et al. eLife 2017). The most promising lncRNA candidates will be further validated and characterized, using the established GONAD procedure, as described in Andergassen and Rinn Nat. Rev. Genet. 2021.
Contribution of the X chromosome to sex bias in cardiovascular disease
Cardiovascular disease (CVD) occurs and progresses differently in men and women, and the risk dramatically increases with age. In women, the finding that CVD occurs less frequent at younger age than post menopause has led to the hypothesis that sex hormones may provide some protection from CVD. However, hormone replacement therapies failed to provide cardioprotection, suggesting that other biological factors contribute to sex disparities in CVD development. Other likely contributors to the sex bias in CVD are genes that escape female X chromosome inactivation. These so-called escaper genes have twice the gene dose in females, compared to males, and thus are likely to contribute to sex-based differences (Andergassen et al. eLife 2017, Andergassen, Dotter et al. NAR 2015). Furthermore, by disrupting epigenetic pathways, we previously demonstrated X-reactivation in vivo (Andergassen, Smith et al. Dev. Cell 2021). The finding that these mechanisms occur during cardiac aging and disease suggests that they may contribute to sex bias in CVD. To test ths hypothesis, we apply allele-specific genomics by combining with genetic mouse models in disease context. This novel strategy will elucidate sex-specific regulation of gene expression by non-coding RNA, and form the basis of new therapies that address the sex bias in cardiovascular disease.