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Elife. 2014 Oct 3;3:e02626. doi: 10.7554/eLife.02626.

Multi-species, multi-transcription factor binding highlights conserved control of tissue-specific biological pathways.

Author information

1
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom.
2
Genetics and Genome Biology Program, SickKids Research Institute, Toronto, Canada.
3
Cancer Research UK-Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
4
School of Electronic and Computing Systems, University of Cincinnati, Cincinnati, United States.
5
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, Australia.
6
Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States.

Abstract

As exome sequencing gives way to genome sequencing, the need to interpret the function of regulatory DNA becomes increasingly important. To test whether evolutionary conservation of cis-regulatory modules (CRMs) gives insight into human gene regulation, we determined transcription factor (TF) binding locations of four liver-essential TFs in liver tissue from human, macaque, mouse, rat, and dog. Approximately, two thirds of the TF-bound regions fell into CRMs. Less than half of the human CRMs were found as a CRM in the orthologous region of a second species. Shared CRMs were associated with liver pathways and disease loci identified by genome-wide association studies. Recurrent rare human disease causing mutations at the promoters of several blood coagulation and lipid metabolism genes were also identified within CRMs shared in multiple species. This suggests that multi-species analyses of experimentally determined combinatorial TF binding will help identify genomic regions critical for tissue-specific gene control.

KEYWORDS:

cis regulatory module; dog; evolutionary biology; genomics; human; human biology; liver; macaque; medicine; molecular evolution; mouse; rat; transcription factors

PMID:
25279814
PMCID:
PMC4359374
DOI:
10.7554/eLife.02626
[Indexed for MEDLINE]
Free PMC Article

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