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.
Below: Hypothetical consequences of variation in transcription factor binding on gene expression: no effect (‘neutral’); altered expression (‘deleterious’); ‘buffering’ by epistatic factors.
Above: 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 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.
Junion G* / Spivakov M*, Girardot C, Braun M, Birney E, Furlong EE. 2012. A transcription factor collective defines cardiac cell fate and reflects lineage history. Cell 148(3): 473-486. (*Joint first authors) [abstract] [pdf] [pubmed]
Spivakov M, Akhtar J, Kheradpour P, Beal K, Girardot C, Koscielny G, Herrero J, Kellis M, Furlong EE, Birney E. 2012. Analysis of variation at transcription factor binding sites in Drosophila and humans. Genome Biology 13: R49. [html] [pdf] [pubmed] [ENCODE threads: 1, 12, 13]
Parelho V* / Hadjur S*, Spivakov M, Leleu M, Gregson H, Jarmuz A, Canzonetta C, Webster Z, Cobb BS, Yokomory K, Aragon L, Dillon N, Fisher AG, Merkenschlager M. 2008. Cohesins functionally associate with CTCF on mammalian chromosome arms. Cell, 132(3): 422-433. (*Joint first authors) [abstract] [pdf] [pubmed]