Long noncoding RNAs regulating development and disease

Overview

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. My lab is 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. Through these studies, we have also developed approaches to screen for compounds that inhibit the fibrotic phenotype in hepatic stellate cells and to screen for coding and noncoding genes that are required to maintain the fibrotic phenotype in hepatic stellate cells. These approaches will allow us to develop new therapies to inhibit liver fibrosis.

Research Projects

My laboratory focuses on understanding how long noncoding RNAs regulate development and disease.

Embryonic stem (ES) cells hold tremendous potential for regenerative medicine. Understanding how long noncoding RNAs regulate ES cell differentiation towards definitive endoderm is key to harnessing the full potential of ES cells and to understanding how mutations of previously unknown genes can lead to disease. We use both genetic and biochemical approaches to study how long noncoding RNAs regulate definitive endoderm differentiation.

Hepatic stellate cells are the primary cell type responsible for liver fibrosis. Hepatic stellate cells are activated and induced to differentiate into hepatic stellate cell myofibroblasts with chronic liver injury. We have mapped the long noncoding RNAs expressed in human hepatic stellate cells and incorporated data from signaling pathways, chromatin structure, and co-expression analysis to identify long noncoding RNAs that are likely to regulate the function of hepatic stellate cells. We are using both genetic and biochemical approaches to study how long noncoding RNAs regulate the function of hepatic stellate cells.

Group Members

Alan Mullen, MD, PhD
Principal Investigator
acmullen@mgh.harvard.edu

Kaveh Daneshvar, PhD
Postdoctoral Fellow
daneshvar.kaveh@mgh.harvard.edu

Chan Zhou, PhD
Postdoctoral Fellow
czhou6@mgh.harvard.edu

Jennifer Chen, MD
Research/Clinical Fellow
jychen@mgh.harvard.edu

Samuel York
Technician
syork1@mgh.harvard.edu

Bo Tan, MD
Visiting Scientist
btan2@mgh.harvard.edu

Publications

View my publications on PubMed.