Long noncoding RNAs in development and fibrosis
Massachusetts General Hospital, Boston, MA
RNA is transcribed from most of the genome, yet only a small fraction of this RNA encodes proteins. More long noncoding RNAs have been annotated in the human genome than protein coding genes, and these numbers continue to increase as long noncoding RNA species are mapped in more cell types. We are focused on understanding how long noncoding RNAs regulate human development and disease. We study the function of long noncoding RNAs in two areas that are relevant to my work as a clinical hepatologist. We study how long noncoding RNAs regulate the differentiation of embryonic stem cells towards definitive endoderm (the first step in development towards the liver and gastrointestinal system), and we study how long noncoding RNAs regulate liver fibrosis. We use genetic approaches to study loss of function through RNA interference and gene disruption using the CRISPR-Cas system and couple this with biochemical approaches to identify the partners that interact with these long noncoding RNAs. In the liver, we study how long noncoding RNAs regulate the fibrotic activity of hepatic stellate cells, the primary cell type responsible for production of the fibrotic scar in chronic liver disease. Recent advances in pluripotent stem cell differentiation now allow us to combine our work in stem cell biology and liver disease through differentiation of pluripotent stem cells into liver organoids to understand how loss of coding and noncoding genes affects liver function. Through these studies, we have also developed approaches to screen for compounds that inhibit the fibrotic phenotype in hepatic stellate cells as well as coding and noncoding genes that are required to maintain the fibrotic phenotype in hepatic stellate cells. These approaches will allow us to better understand the function of long noncoding RNAs and develop new therapies to inhibit liver fibrosis.