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 organisational and functional 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 initiated through diverse cues modulating transcription factor activity, which converge on cis-regulatory elements such as enhancers. Enhancers thereby 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
Our research focuses on dissecting general mechanisms of transcriptional regulation, including how the cis-regulatory genome is organised within 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 multi-cellular embryo; Drosophila mesoderm specification.
Future projects and goals
Chromatin topology – the 3D Genome
How our huge genome is packaged within the confined space of the nucleus to facilitate transcription remains a key challenge in genome regulation. For enhancers to function, they must come in proximity to their target genes. We recently discovered a surprising stability of these ‘looping’ interactions during two stages of embryonic development (Nature 2014). Going forward, we will examine this over an extensive developmental time-course, integrating high-resolution imaging and genetics to dissect the relationship between proximity and transcriptional regulation.
Chromatin remodelling during cell fate decisions
To uncover general properties of enhancer function 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). Going forward, we will combine this technology with single cell methods and CRISPR/Cas9 technology to understand regulatory properties associated with developmental transitions.
Variation and plasticity in regulatory networks
Variation in the non-coding genome is widely associated with Quantitative Trait Loci and GWAS loci. Many of these disease-associated variants are in cis-regulatory elements, yet it is very difficult to pinpoint the causal SNP within the human genome and therefore dissect the underlying mechanism. We are developing methods to bridge this gap, taking advantage of the extremely high sequence variation among wild Drosophila isolates, to dissect functional regulatory variants involved in transcription and genome organisation during embryonic development.
|ERC ADVANCED INVESTIGATOR|