Regulatory Genomics and Cancer Evolution

Division of Regulatory Genomics and Cancer Evolution

Dr. Duncan Odom

Comparing the functionof genetic sequences among mammals can reveal the mechanisms of normal and cancer evolution. Image courtesy of C Ernst.
© dkfz.de

Dr Odom’s laboratory studies how genetic sequence information shapes the cell's DNA regulatory landscape and thus the trajectory of cancer genome evolution. Our interspecies analysis of matched functional genomic data has revealed the extensive and rapid turn-over of tissue-specific transcription factor binding, insulator elements, polymerase occupancies, and enhancer activities during organismal evolution. To demonstrate that genetic sequences were the major determinant of transcription and transcriptional regulation, the Odom lab re-purposed a fascinating aneuploidy mouse model of Down syndrome that carries an almost complete copy of human chromosome 21. Profiling the functional behaviour of a human chromosome in a mouse nucleus provided an elegant and powerful demonstration that cis-acting sequences have a greater impact than trans influences on transcription factor binding, chromatin state, and gene expression. Recently, his laboratory has begun exploiting single-cell RNA-sequencing and large-scale whole genome sequencing in understanding molecular evolution. Recent high-profile studies from the Odom lab used single-cell transcriptional analysis to conclusively demonstrate that ageing results in substantial increases in cell-to-cell transcriptional variability, and we have undertaken large-scale analysis of how genetic and epigenetic differences between alleles can alter cancer mutagenesis.

Our ongoing work is focused on three major areas. First, we continue to explore how genetic sequence variation shapes genome regulation and gene expression in normal somatic tissues, by comparing examples from closely related and distantly related mammals. We are actively developing novel approaches that exploit recently developed single-cell transcriptional and epigenomic approaches, as well as controlled CTCF perturbations [funded by an ERC Advanced Grant]. Second, we are currently using chemical carcinogenesis to create and analyse liver tumours in multiple different mammalian species. This approach is, to our knowledge, the first large-scale strategy to create carefully controlled tumour cohorts that can be reliably and quantitatively compared to reveal the underlying principles of cancer genome evolution. Third, we are testing how ageing interacts with genetic diversity in shaping genome stability using a set of closely related mouse species with a similar organismal phenotype, but with highly divergent genomes. These scientific themes have substantial latitude to tailor particular projects to suit the scientific interests of incoming students and postdocs.

Contact

Dr. Duncan Odom
Regulatory Genomics and Cancer Evolution (B270)
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 280
69120 Heidelberg
Tel: +49 6221 42 3446

Selected Publications

  • S. Aitken, X. Ibarra-Soria, E. Kentepozidou, P. Flicek, C. Feig, J. Marioni, D. T. Odom. (2018) CTCF maintains regulatory homeostasis of cancer pathways. Genome Biology, 106-114.
  • C. Martinez-Jimenez, N. Eling, ... J. C. Marioni, D. T. Odom. (2017) Aging increases cell-to-cell transcriptional variability upon immune stimulation. Science, 1433-1436.
  • D. Villar, C. Berthelot, ... P. Flicek, D. T. Odom. (2015) Enhancer evolution across twenty mammalian species. Cell, 554-563.
  • K. Stefflova, D. Thybert, ... P. Flicek, D. T. Odom. (2013) Cooperativity and rapid evolution of co-bound transcription factors in closely related mammals. Cell, 530-540.
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