Odom:Research

In general, we take an integrative approach, combining genome-wide transcription factor binding, gene expression perturbation using genetic manipulations, comparative genomics, and physiological approaches to understand on a systems-wide basis how a tissue is defined. To date, our work has revealed the core circuitry of human hepatocytes and pancreatic islets, begun assessing how small collections of transcriptional regulators can dictate cellular biology, and preliminarily revealed the connections that exist between miRNA programs and transcription factor binding events.

Transcription and transcriptional regulatory evolution in mammals
Recent results suggests that few transcription factor-DNA interactions appear to be evolutionarily maintained in mammals, yet most evidence suggests that the gene expression programs of particular tissues are highly conserved. My laboratory, in collaboration with a number of other laboratories, continues to explore the regulatory mechanisms that can maintain specific transcriptional programs in spite of genetic evolutionary drift and subsequent divergence of transcription factor binding in vivo.

Collaborators: Flicek/EBI, Blencowe/UToronto, Fraenkel/MIT, Gifford/MIT, Tavare/CRI

noncoding RNA conservation and evolution
We are also investigating the transcriptional regulation and evolution of numerous types of noncoding RNAs. These riboregulators range from well-known classes such as microRNAs and transfer RNAs to more recently discovered species such as long intergenic noncoding RNAs. We are applying approaches similar to those used in looking at transcrition factor binding evolution and transcriptional evolution of mRNAs to understanding how these additional layers of genomic regulation evolve. Collaborators: Brazma/EBI, Marioni/EBI, Ponting/Univ Oxford, Ule/LMB

Determinants of tissue-specific transcriptional regulation
Sets of conserved transcription factors are responsible for conserved tissue-specific transcription, yet transcription factor binding events diverge rapidly between closely related species. To decouple the distinct molecular mechanisms that direct transcription factor binding and gene expression we investigated tissue-specific transcriptional regulation in a mouse containing human chromosome 21 (the Tc1 mouse). Gene expression and transcription intiation occurs at similar syntenic genes in hepatocytes from humans, wild-type mice, and Tc1 mice; however, the transcription initiation occurring in other genomic regions is specified by species-specific genetic sequences. Characterization of transcription factor binding in the Tc1 mice reveals that tissue-specific transcriptional regulation is directed almost exclusively by species-specific genetic sequences. Divergent patterns of transcriptional regulation coded in genetic sequence can thus be transplanted between species to recapitulate conserved transcription in homologous tissues.

Collaborators: Fisher/UCL, Tavare/CRI, Tybulewicz/NIMR