Gene expression is regulated through a sophisticated network of interactions between protein-coding gene promoters and distal cis-regulatory sequences such as enhancers. The Adelman lab is actively engaged in probing how these interactions are established and how they control transcription profiles during development and in response to external signals. Gaining this information is critical to develop treatments for cancer and other diseases where transcription becomes dysregulated.
The Adelman group pioneered global studies of Pol II pausing during early transcription elongation. Pausing, and the regulated release of Pol II into productive RNA synthesis have emerged as central aspects of mRNA synthesis, and our recent work has demonstrated the importance of pause regulation at enhancers as well. We hypothesize that paused Pol II plays similar roles at promoters and enhancers: maintaining accessible chromatin; stabilizing a scaffold of general transcription factors; and presenting nascent RNA for interaction with transcription and epigenetic regulators.
RNA polymerase II transcribes RNA at both promoters and enhancers. However, the RNA species generated at promoters and enhancers have dramatically different fates: the vast majority of non-coding RNAs are short RNAs that are degraded rapidly after synthesis. Understanding how productive RNA elongation and termination are regulated differently at genes and enhancers, and how the distinct RNA species generated impact cellular behavior are central goals of the Adelman lab. We are embarking on both experimental and computational searches for the underlying principles that define the processivity of Pol II and how the fate and function of nascent RNA is determined.
We are also using nascent RNA sequencing techniques (e.g. PRO-seq) to identify enhancers in cancer cells, and following treatment with anti-cancer drugs. This information sheds new light on how abnormal gene expression programs are established in cancer, and how resistance to therapeutics is developed.
Ongoing work explores how transcription elongation interfaces with epigenetic features and genome organization. We are investigating:
- Transcription elongation and pausing
- Co-transcriptional splicing and Transcription termination
- Chromatin remodeling by SWI/SNF
- Epigenetic modifications of histones at promoters and enhancers
- Roles of cohesin in regulating gene activity and RNA processing
Approaches include cutting-edge genomic, biochemical and bioinformatic strategies to further elucidate gene regulation at promoters and enhancers, and models of inflammation, cancer and development.