Research Overview
Our research is focused on identifying and characterizing new mechanisms of RNA regulation in the dynamic control of gene expression. We apply this knowledge to explore how RNA regulatory pathways impact stem cell pluripotency, mammalian development, growth, cancer, and neurological diseases. Ultimately we aim to exploit this understanding for the development of new therapeutic approaches for cancer and degenerative disease.
Research in our lab encompasses three broad areas of investigation:
Bridging RNA biochemistry/molecular biology & stem cell research
Our specialized research program bridges RNA biochemistry/molecular biology and stem cell research at the forefront of an exciting area of investigation focused on the regulation of microRNAs (miRNAs), messenger RNAs (mRNAs), and long non-coding RNAs (lncRNAs). We have made significant contributions to identifying and characterizing key molecular and cellular mechanisms of stem cell biology including the regulation of let-7 miRNAs by the RNA-binding protein and pluripotency factor LIN28. Pluripotent embryonic stem cells (ESCs) have the capacity to differentiate into any specialized cell type and are of potential therapeutic value for numerous degenerative diseases. Relatively little is known about the posttranscriptional mechanisms controlling ESC biology. Identifying novel gene regulatory pathways required for ESC self-renewal and pluripotency will define the foundations of ESC biology and facilitate the effective manipulation of cell fates for novel therapeutic approaches. Moreover, ESCs provide the opportunity to study developmentally controlled gene regulatory pathways and are amenable to applying biochemical, genetic, and cell biological approaches to elucidate these mechanisms.
RNA biogenesis & decay pathways
We investigate how alterations in RNA biogenesis and decay pathways contribute to human disease. Until recently the lab has focused primarily on the regulation of tumor suppressor (let-7) and oncogenic (miR-17~92) miRNAs in cancer. We are currently broadening the scope of our work to include additional disease genes and pathways impacting RNA metabolism. Our innovative research strategy addresses areas that are new, unexplored, and poorly understood. As pioneers studying several disease-relevant RNA-binding proteins and ribonucleases, the lab is uniquely poised to make fundamental and groundbreaking discoveries. As new pathways and pathogenic RNAs are identified we design, develop, and perform high-throughput small molecule screening assays for the identification of new drug-like molecules that can restore RNA expression as a possible novel therapeutic approach.
RNA methylation in gene regulation and disease
Over the last thirty years much work has been done on understanding how DNA methylation, and histone modifications influence gene expression. Many of the relevant enzymes that catalyze the deposition (‘writers’) or removal (‘erasers’) of these epigenetic marks have been identified, as well as ‘reader’ proteins that specifically bind to certain chromatin modifications. There is now widespread evidence of epigenetic dysregulation in cancer, in which histone and DNA modification play a critical role in tumor growth and survival. Indeed, drugs that alter DNA methylation by inhibiting the DNA methyltransferases (MTase) are used clinically to treat various malignancies. It is emerging that RNAs are also subject to various posttranscriptional modifications. For example, recent studies reported that N6-Methyladenosine (m6A), the most abundant mRNA modification, regulates mRNA splicing, export, stability and translation. Studies aimed at defining RNA modifications throughout the transcriptome and elucidating the molecular and cellular function of individual modifications has led the emergence of the nascent field of ‘epitranscriptomics’. We recently provided the very first functional evidence linking the epitranscriptome with cancer. This work represents the basis for ongoing efforts to elucidate the role of the molecular and cellular mechanisms of the epitranscriptome in cancer and to identify pharmacological methyltransferase inhibitors towards the development of new drugs targeting the epitranscriptome as a cancer therapy.
Our goal is to understand the role of RNA methylation in human cancer cells, primary tumors, and mouse models, and to establish assays suitable for high throughput screening to identify small molecule inhibitors of these pathways as a novel cancer therapeutic strategy. To accomplish our ambitious and groundbreaking goal we will address the following five questions to guide our new strategic direction.
- How does mRNA methylation regulate mRNA expression?
- Is mRNA methylation dysregulated in human tumors?
- What mechanism(s) might be responsible for altered mRNA methylation in cancer?
- Can altered mRNA methylation promote tumorigenesis?
- Can we identify small molecule inhibitors to manipulate mRNA methylation in cancer?