Cell-type and condition-specific patterns of gene expression are established 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 the many diseases where transcription becomes dysregulated.
Interestingly, RNA polymerase II is recruited to and 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 (<120nt) RNA species that are degraded shortly after release. Understanding how the processes of productive RNA elongation and termination are regulated differently at genes and enhancer regions, 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 how the processivity of Pol II and fate of the nascent RNA is determined.
In addition, we are taking genomic approaches to identify enhancers in varying developmental stages and disease states using nascent RNA sequencing techniques (Start-seq, PRO-seq). This information on the location and sequence context of regulatory regions sheds new light on gene expression profiles, local epigenetic features, and three-dimensional chromatin architecture.
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.
Ongoing work will further explore how RNA polymerase elongation impacts epigenetic features and organization of the genome. Approaches include cutting-edge genomic and bioinformatic strategies to further elucidate gene regulation at promoters and enhancers, and mouse models of inflammation and development.