- epigenetic control by long noncoding RNAs, genomics, stem cells, cancer, human genetic disorders
Several conserved, long noncoding RNAs (lncRNAs) play essential roles in mammalian development through their ability to coordinately silence, at the level of transcription, clusters of spatially adjacent protein coding genes. The flagship example is Xist, which orchestrates the silencing of nearly all genes along the 165 million base pair inactive X chromosome, but a handful of other lncRNAs, including Kcnq1-Overlapping-Transcript-1 (Kcnq1ot1) and Antisense-of-IGF2R-noncoding-RNA (Airn), perform similar functions within smaller genomic intervals. Collectively, the misregulated expression of genes targeted for silencing by these lncRNAs results in a group of genetic disorders that affect millions of individuals world-wide. Many of these diseases are untreatable beyond palliative measures despite knowledge of their underlying cause. More broadly, thousands of regions in the human genome produce unstudied RNAs that have little potential to encode for protein, suggesting additional physiologically relevant examples of lncRNA-mediated transcriptional control remain to be discovered. Work in the Calabrese lab aims to delineate, in molecular detail, the mechanisms by which Xist and related lncRNAs silence transcription. We are also developing experimental and computational tools to determine the fraction of the genome subject to silencing by Xist-like lncRNAs in normal and cancerous cells, and to discover methods to modulate their biological activity. We expect our work to uncover molecular details of gene regulatory events whose alteration gives rise to human disease and to suggest novel avenues to manipulate transcriptional outcomes in regions of the human genome that are essential for normal health and development.
Motivated graduate students and post-doctoral fellows interested in joining the group are encouraged to contact Dr. Calabrese via email.