Life Sciences Research for Lifelong Health

The logic and robustness of gene regulation

Cells in the body share the same genotype, but express an amazing diversity of phenotypes in time and space. Global analyses of transcription factor binding, chromatin state and long-range chromatin interactions have streamlined the annotation of DNA regulatory modules – ‘switches’ of gene expression. However, we still know rather little about how exactly these modules work. In particular, it remains to be understood how the input of different regulators, such as cooperating transcription factors and chromatin modifiers, is integrated on the DNA sequence.

The majority of SNPs identified in genome-wide association studies for healthy and pathological traits do not implicate a protein-coding variant, emphasizing the importance of understanding regulatory DNA sequence. And yet many non-coding mutations, even within evolutionary conserved regions, have little to no phenotype. Are all of these mutations genuinely neutral or, rather, are their effects ‘buffered’ by other parts of the regulatory network? If so, how exactly do these compensatory mechanisms work, and are they impaired under certain conditions such as age?

​Our group studies these questions using a combination of functional genomics and population genetics approaches, with a particular focus on computational analyses and on mammalian development and ageing as experimental systems.

Figure shows the ‘TF collective’ model of enhancer organisation (Junion/Spivakov et al., 2012) in comparison with other proposed models – ‘billboard’ (Kulkarni and Arnosti, 2003) and ‘enhanseosome’ (Thanos and Maniatis, 1995).
The TF collective model