Dr Daniel Bose
Sir Henry Dale Research Fellow
The patterns of genes expressed in multicellular organisms are crucial for determining a cell’s identity, and for controlling environmental responses. Gene transcription is regulated at regions adjacent to genes called promoters, but also from regions called enhancers that are often located tens-of-thousands of base-pairs away from the promoter. Enhancers are fundamental regulatory DNA sequences; they are crucial for driving development, and for generating cell-lineage specific transcriptional responses to environmental stimuli.
Across the genome, enhancers have unique activities and their mutation and aberrant usage is causative for many human diseases, including cancer. Enhancers that actively promote transcription have a unique chromatin environment and produce non-coding RNA transcripts known as enhancer RNAs (eRNAs). Our work has shown how eRNAs can interact with epigenetic-enzymes – the enzymes responsible for modifying chromatin to control gene expression – to stimulate enhancer activity. Our results suggest that eRNAs are critical drivers of enhancer-specific activity profiles. Moreover, disease-related mutations at enhancers could fundamentally alter interactions between eRNAs and enzymes to disrupt enhancer activity.
Figure 1: How eRNA stimulates CBP activity.
Our work demonstrated that eRNAs bind to a regulatory region within the catalytic acetyltransferase domain of the key transcription co-activator CBP. By displacing this region from the active site of the enzyme, eRNAs could stimulate the acetyltransferase activity and promote histone acetylation and transcription.
The Bose lab is interested in the diverse mechanisms used by eRNAs to regulate the core epigenetic-machinery and drive different enhancer functions. We use a multidisciplinary approach, incorporating state of the art functional genomics, biochemistry and single particle cryo-EM. By combining structural analyses with in vitro and in vivo data, we are able to build a detailed, mechanistic understanding of how interactions between eRNAs and epigenetic-enzymes can generate tailored patterns of enhancer activity and gene expression.
Figure 2: How do eRNAs affect enhancer activity?
As the sequence and structure of eRNAs differs between enhancers, they are prime candidates to drive alternative profiles of enhancer activity to control gene expression.
Gene-regulation; chromatin modification; enhancers; eRNA; non-coding RNA; RNA-binding; epigenetic-enzymes; histone acetylation; CBP/p300; acetyltransferase; cryo-EM; functional genomics; biochemistry.
- Bose, D.A., Donahue, G., Reinberg, D., Shiekhattar, R., Bonasio, R., and Berger, S.L. (2017). RNA Binding to CBP Stimulates Histone Acetylation and Transcription. Cell 168, 135–149.e22. (View abstract)
- Adelman, K., and Egan, E. (2017). Non-coding RNA: More uses for genomic junk. Nature 543, 183–185. (View abstract)
- Saravanan, M*., Wuerges, J*., Bose, D*., McCormack, E.A., Cook, N.J., Zhang, X., and Wigley, D.B. (2012). Interactions between the nucleosome histone core and Arp8 in the INO80 chromatin remodeling complex. PNAS 09, 20883-8. (* Joint first author) (View abstract)
- Klein, B.J*., Bose, D*., Baker, K.J., Yusoff, Z.M., Zhang, X., and Murakami, K.S. (2011). RNA polymerase and transcription elongation factor Spt4/5 complex structure. PNAS 108, 546–550. (* Joint first author) (View abstract)
- Bose, D., Pape, T., Burrows, P.C., Rappas, M., Wigneshweraraj, S.R., Buck, M., and Zhang, X. (2008). Organization of an activator-bound RNA polymerase holoenzyme. Mol Cell 32, 337–346. (View abstract)