Figure 1: Enhancers interact with genes over very long distances within the Drosophila genome, as shown by 4C-Seq (top) and DNA FISH (bottom) during embryogenesis (Ghavi-Helm Y, et al., Nature 2014).
Figure 2: Chromatin state and Pol II occupancy on enhancers (yellow) is highly predictive of enhancers’ activity, with Pol II being predictive for the precise timing during development (Bonn*, Zinzen*, Girardot*, et al., Nature Genetics 2012).
The Furlong group dissects fundamental principles of transcriptional regulation, and how that drives cell fate decisions during development, focusing on functional and organisational properties of the genome.
Previous and current research
Precise regulation of gene expression is essential for almost all biological processes, and a key driving force in development, evolution and disease. Expression states are initially established through the integration of environmental cues (signalling pathways) with transcriptional networks, which converge on cis regulatory elements called enhancers. Enhancers therefore act as integration platforms to control specific patterns of expression, telling genes when and where to be expressed. Given their central role, mutations in enhancers often lead to devastating developmental defects and are becoming increasingly linked to human disease
Much of our research focuses on mechanisms of enhancer function, including how the cis-regulatory genome is organised with the nucleus (Figure 1), and how chromatin state and transcription factor occupancy influence this process (Figure 2). We investigate how natural sequence variation (both within and between species) affects transcription, leading to specific phenotypes. Our work combines genomic, genetic and computational approaches to understand these processes, including the development of new genomic tools to facilitate this analysis within the context of a multicellular embryo, Drosophila mesoderm specification.
Future projects and goals
Chromatin remodelling during cell fate decisions: To uncover general properties of enhancer function during embryogenesis, we developed a method to investigate cell type-specific changes in chromatin state in the context of a multicellular embryo’s development (Figure 2; Nature Genetics, 2012). Using this method, we are currently dissecting the interplay between changes in chromatin remodelling, transcription factor and Pol II occupancy with dynamic changes in developmental transitions.
Enhancer looping and 3D Genome Topology: For enhancers to function, they must come in proximity to their target gene’s promoter. This often results in the ‘looping out’ of intervening DNA. We have recently examined this within two time-points of development (Nature 2014), and discovered extensive long-range interactions within the compact Drosophila genome, and a surprisingly stability of these interactions during these stages of development. We will build on this, looking at enhancer topology during a much longer developmental time-span, integrating high-resolution imaging to understand the relationship between proximity and transcriptional regulation.
Variation and plasticity in cis-regulatory networks: Variation in cis-regulatory elements can affect gene expression and account for individual differences in phenotypes. However, little is known about how much variation is tolerated during essential developmental processes during embryonic development. We are investigating this by determining the extent to which natural sequence variation among wild isolates, and nearby species, affects embryonic development at a transcriptional and genome organisational level.
|ERC ADVANCED INVESTIGATOR|