Research Overview

Our laboratory studies the transcriptional and epigenetic control of gene expression in mammalian cells. We use a combination of genetic, biochemical and computational methods to investigate gene control in healthy cells and to ascertain how these controls go awry in disease. The molecular apparatuses and mechanisms that control gene expression programs in early development and in cancer are of particular interest. Learning how gene expression programs are regulated is important for understanding the control of cell state, the process of development and the mechanisms that underlie disease (Lee and Young, 2013).

The laboratory has developed powerful genomics methods to investigate how gene expression programs are controlled by transcription factors, chromatin regulators and signaling pathways. Our studies in embryonic stem cells revealed that master transcription factors form a core circuitry that regulates pluripotency, communication between enhancers and promoters is promoted by DNA looping cofactors, regulatory RNAs facilitate transcription factor binding, and developmental signaling pathways connect directly to the enhancers of key genes (Boyer et al., 2005; Boyer et al., 2006; Lee et al., 2006; Marson et al., 2008; Kagey et al., 2010; Rahl et al., 2010; Mullen et al., 2011; Sigova et al., 2015). We discovered that large clusters of enhancers, which we call super-enhancers, regulate genes that play the most prominent roles in cell identity (Whyte et al., 2013; Hnisz et al., 2015). Super-enhancer driven genes occur in "insulated neighborhoods", where large DNA loops serve to maintain proper expression of genes within and outside of the loop (Dowen et al., 2014; Ji et al., 2015; Hnisz et al., 2016).

Our laboratory is also interested in transcriptional disregulation in cancer. We discovered that oncogenic c-Myc causes transcriptional amplification: c-Myc binds to the promoters of active genes in tumor cells and enhances pause release, thereby increasing the transcriptional output of all genes (Lin et al., 2012). We also found that tumor cells acquire especially large super-enhancers at driver oncogenes, and that they do so by multiple mechanisms, including somatic monoallelic insertion of sequences that bind master transcription factors (Hnisz et al., 2013; Mansour et al., 2014). These oncogenic super-enhancers encompass large domains, sometimes spanning more than 100 kb, and are highly vulnerable to transcriptional inhibitors (Lovén et al., 2013; Kwiatkowski et al., 2014; Wang et al., 2015). This vulnerability is due to the loss of highly cooperative interactions at large oncogenic super-enhancers, with subsequent loss of expression of short-lived oncogene transcripts.

These studies form the foundation for improved understanding of cellular regulation in human health and disease, for efforts to reprogram cells for regenerative medicine, and for development of new therapies for cancer.