The cellular abundances of RNAs are strictly controlled in time and space. Transcription initiation is regulated in part by events proximal to gene promoters, where transcription factors (TFs) bind specific DNA sequences and collectively promote the recruitment of RNA polymerase II. Enhancers, regulatory elements remote from gene transcription start sites, provide additional input to the correct expression of genes. The activities of each regulatory element (enhancer and/or promoter function) are determined by the local DNA sequence and chromatin accessibility, its bound TFs, and the chromatin architectures bringing genomically distant regulatory elements close to their targets in three-dimensional space. The resulting specific topology of regulatory elements and their activities provide a way for cells to achieve specific transcriptional programs. As a consequence, regulatory and transcriptional activities may vary drastically between cells and change in response to stimuli. Despite considerable advancement in the field during the last decade, the composition of regulatory topologies and their activities, the interplay between involved regulatory elements, and their individual functions remain to a large degree poorly understood.
Regulatory active enhancers are transcribed into enhancer RNAs (eRNAs) and we have utilized this phenomenon to established an accurate approach to infer enhancer locations and their activities from eRNA 5’ ends sequencing data. This eRNA-centered approach has laid the foundation for several projects in the group, allowing us to use eRNAs as a proxy for enhancer activity to study cell-type specific regulation, the impact of genetic variants on transcriptional regulation, the importance of single-element enhancer activities and the role they play in larger regulatory architectures to define cell-type specific transcriptional activities.
Our results indicate that gene promoters and enhancers share many properties, which challenge the enhancer-promoter dichotomy in the field. We know today that the majority of active metazoan enhancers and gene promoters are divergently transcribed and that both enhancer and gene transcription initiate at core promoter elements. Our work suggests a unified promoter architecture of regulatory elements, whose regulatory functions might not be discernible on a per-element basis. Rather, some regulatory elements possess both strong enhancer and strong promoter function, while others are characterized by strong enhancer function and weak promoter function or vice versa.
The main aim of the Andersson lab is to better understand the logics of regulatory elements and their architectures. To this end, we perform computational analyses and modelling of transcriptional regulation based on large-scale sequencing of transcription initiation events and other genomics data. Our long-term focus is on three aspects of transcriptional regulation:
- the determinants of enhancer and promoter function
- the importance of individual regulatory elements
- the roles of encompassing regulatory architectures
- Andersson R, et al. 2014. An atlas of active enhancers across human cell types and tissues. Nature. DOI
- Andersson R, et al. 2014. Nuclear stability and transcriptional directionality separate functionally distinct RNA species. Nat Comms. DOI | preprint
- Arner E, et al. 2015. Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells. Science. DOI
- Andersson R. 2015. Promoter or enhancer, what’s the difference? Deconstruction of established distinctions and presentation of a unifying model. BioEssays. DOI
- Andersson R, et al. 2015. A Unified Architecture of Transcriptional Regulatory Elements. Trends Genet. DOI | preprint
- Rennie S, et al. 2018. Transcription start site analysis reveals widespread divergent transcription in D. melanogaster and core promoter-encoded enhancer activities. Nucleic Acids Res. DOI | preprint