Regulatory evolution in mammalian tissues - Associate Faculty group

Duncan Odom's Associate Faculty group compares how transcription and transcriptional regulation vary during evolution, and the implications this regulatory plasticity has for diseases such as cancer.

We compare how transcription and transcriptional regulation vary during evolution, and the implications this regulatory plasticity has for diseases such as cancer. We use numerous new high throughput methods combined with analysis of multiple mammals and vertebrates to reveal fundamental biological insights into tissue-specification and genome evolution.

[Wikimedia Commons]

Background

The wide variety in forms and functions among animals we see today is profoundly linked with diseases such as cancer by the simple fact that they originate from a common source: differences in DNA.

Enormous efforts are being put forth to identify the mutations associated with cancers, but one of the most formidable challenges today is understanding what these mutations do (or, more often, do not do). There is still a very poor understanding of which changes in the genome are harmless, and which have an effect of some kind, either good or bad. We analyze how very divergent genomes from different species can create the same, highly conserved cell type, liver, and what lessons this conservation holds for understanding the biology of the genome.

Research

Many different kinds of proteins interact with the mammalian genome to direct transcription of specific cell types. These protein-DNA interactions range from very precise, yet widespread binding of tissue-specific transcription factors, to the anchorage-like binding of insulator proteins such as CTCF and NRSF, to the basic transcriptional machinery of the polymerases.

The tRNA genes bound by Pol III diverge in genomic location and functional usage among mammals.

The tRNA genes bound by Pol III diverge in genomic location and functional usage among mammals. [doi:10.1038/ng.906]

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To gain insight into how transcription, evolution, and the rapidly evolving genome interact, the Odom laboratory (along with our collaborators) have used comparisons of all these layers of transcriptional regulation both:

  • among different cell types within one species
  • among the same cell type from many species

For instance, we have discovered that mammalian transcription factors rarely, if ever, show high conservation in transcription factor binding, as was previously expected. In contrast, insulators are much more frequently conserved, but are subject to lineage-specific, large-scale remodelling based on activation of repeat elements in the genome. At the level of the basal machinery, by investigating how RNA polymerase III regulates tRNAs in multuple mammals, we have discovered that the polymerases responsible for gene expression may be under constraint at the level of their transcripts, the mechanism for which we are actively investigating.

Our ongoing work at the Sanger Institute will produce a cross-sectional view of the liver epigenome for a wide variety of vertebrates. In addition, we have begun an integrated cancer systems biology project that combines the high-throughput experimental expertise at the Wellcome Trust Sanger Institute with the cancer biology approaches from Cancer Research UK's Cambridge Research Institute.

Collaborations

In addition to many collaborators at Sanger and The Cambridge Research Institute (CRI), we also work closely with a number of sister groups, including those of:

Selected Publications

  • Waves of retrotransposon expansion remodel genome organization and CTCF binding in multiple mammalian lineages.

    Schmidt D, Schwalie PC, Wilson MD, Ballester B, Gonçalves A, Kutter C, Brown GD, Marshall A, Flicek P and Odom DT

    Cell 2012;148;1-2;335-48

  • Pol III binding in six mammals shows conservation among amino acid isotypes despite divergence among tRNA genes.

    Kutter C, Brown GD, Gonçalves A, Wilson MD, Watt S, Brazma A, White RJ and Odom DT

    Nature genetics 2011;43;10;948-55

  • Five-vertebrate ChIP-seq reveals the evolutionary dynamics of transcription factor binding.

    Schmidt D, Wilson MD, Ballester B, Schwalie PC, Brown GD, Marshall A, Kutter C, Watt S, Martinez-Jimenez CP, Mackay S, Talianidis I, Flicek P and Odom DT

    Science (New York, N.Y.) 2010;328;5981;1036-40

  • A CTCF-independent role for cohesin in tissue-specific transcription.

    Schmidt D, Schwalie PC, Ross-Innes CS, Hurtado A, Brown GD, Carroll JS, Flicek P and Odom DT

    Genome research 2010;20;5;578-88

  • Evolution of transcriptional control in mammals.

    Wilson MD and Odom DT

    Current opinion in genetics & development 2009;19;6;579-85

  • Species-specific transcription in mice carrying human chromosome 21.

    Wilson MD, Barbosa-Morais NL, Schmidt D, Conboy CM, Vanes L, Tybulewicz VL, Fisher EM, Tavaré S and Odom DT

    Science (New York, N.Y.) 2008;322;5900;434-8

  • Tissue-specific transcriptional regulation has diverged significantly between human and mouse.

    Odom DT, Dowell RD, Jacobsen ES, Gordon W, Danford TW, MacIsaac KD, Rolfe PA, Conboy CM, Gifford DK and Fraenkel E

    Nature genetics 2007;39;6;730-2

  • Control of pancreas and liver gene expression by HNF transcription factors.

    Odom DT, Zizlsperger N, Gordon DB, Bell GW, Rinaldi NJ, Murray HL, Volkert TL, Schreiber J, Rolfe PA, Gifford DK, Fraenkel E, Bell GI and Young RA

    Science (New York, N.Y.) 2004;303;5662;1378-81

* quick link - http://q.sanger.ac.uk/pbg7x9q8