Research

Activating transcriptional regulatory elements are essential for proper cellular activities during development, for maintaining homeostasis, and for accurate response to external stimuli. They act via promoter and enhancer activities, with the former defining where transcription is initiated and the latter amplifying transcription. Regulatory elements bind transcription factors (TFs), which in turn promote the recruitment and transcription initiation of RNA polymerase II locally or at proximal loci in the cell nucleus. The activity of each regulatory element is thus influenced by its DNA sequence and chromatin accessibility, its bound TFs and a favorable chromatin topology bringing it close to other regulatory elements in three-dimensional space.

In line with their importance, regulatory elements overlap with genetic variants underlying transcriptional variation and other phenotypic traits in pathologically relevant cell types, and their alterations have been implicated in several congenital diseases and cancers. In fact, a large proportion of genetic diseases cannot directly be linked with exonic, protein-coding base pair changes, indicating that many diseases may be associated with disruptions of regulatory activities rather than changes in peptide sequences. However, fine mapping and interpretation of such events have proven to be very challenging, due to a general lack of understanding how regulatory function and activity is determined by DNA sequence and the encompassing chromatin topology. Understanding the functions and interplay of regulatory elements and the determinants of their activity is therefore of major importance to the field.

We have shown that classically defined enhancers and promoters share several properties and functions. For example, their chromatin and sequence architectures are remarkably similar, there are prototypical examples of gene promoters with enhancer activity, and regulatory active enhancers are able to initiate local transcription themselves, thereby working as promoters. In fact, we have shown that enhancer transcription (eRNAs), detected using transcription start site profiling by Cap Analysis of Gene Expression (CAGE), is a much better predictor of enhancer activity than chromatin characteristics (up to 3-fold increase in in vitro validation rate). Our results suggest that regulatory elements should therefore be considered a unified class of elements with varying degrees of non-mutually exclusive regulatory functions.

We have utilized the phenomenon of enhancer transcription to established an accurate approach to infer the locations of regulatory elements and their enhancer activities from eRNA 5’ end 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 individual enhancers and the role they play in larger regulatory topologies to define cell-type specific transcriptional activities.

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Figure from Andersson R, Sandelin A. 2019. Nature Review Genetics.

Aims

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 data of transcription initiation events and other genomics data. Our long-term focus is on three aspects of transcriptional regulation:

  1. the determinants of enhancer and promoter function
  2. the importance of individual regulatory elements
  3. the roles of encompassing regulatory architectures

Defining work

  • 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
  • Andersson R, Sandelin A. 2019. Determinants of enhancer and promoter activities of regulatory elements. Nat Rev Genet 337: 1–17. DOI

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