Abstract
BackgroundExperimentally validated data on gene regulation are hard to obtain. In particular, information about transcription factor binding sites in regulatory regions are scattered around in the literature. This impedes their systematic in-context analysis, e.g. the inference of their conservation in evolutionary history.ResultsWe demonstrate the power of integrative bioinformatics by including curated transcription factor binding site information into the UCSC genome browser, using wiki and custom tracks, which enable easy publication of annotation data. Data integration allows to investigate the evolution of gene regulation of the pluripotency-associated genes Oct4, Sox2 and Nanog. For the first time, experimentally validated transcription factor binding sites in the regulatory regions of all three genes were assembled together based on manual curation of data from 39 publications. Using the UCSC genome browser, these data were then visualized in the context of multi-species conservation based on genomic alignment. We confirm previous hypotheses regarding the evolutionary age of specific regulatory patterns, establishing their "deep homology". We also confirm some other principles of Carroll's "Genetic theory of Morphological Evolution", such as "mosaic pleiotropy", exemplified by the dual role of Sox2 reflected in its regulatory region.ConclusionsWe were able to elucidate some aspects of the evolution of gene regulation for three genes associated with pluripotency. Based on the expected return on investment for the community, we encourage other scientists to contribute experimental data on gene regulation (original work as well as data collected for reviews) to the UCSC system, to enable studies of the evolution of gene regulation on a large scale, and to report their findings.ReviewersThis article was reviewed by Dr. Gustavo Glusman and Dr. Juan Caballero, Institute for Systems Biology, Seattle, USA (nominated by Dr. Doron Lancet, Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel), Dr. Niels Grabe, TIGA Center (BIOQUANT) and Medical Systems Biology Group, Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Germany (nominated by Dr. Mikhail Gelfand, Department of Bioinformatics, Institute of Information Transfer Problems, Russian Academy of Science, Moscow, Russian Federation) and Dr. Franz-Josef Müller, Center for Regenerative Medicine, The Scripps Research Institute, La Jolla, CA, USA and University Hospital for Psychiatry and Psychotherapy (part of ZIP gGmbH), University of Kiel, Germany (nominated by Dr. Trey Ideker, University of California, San Diego, La Jolla CA, United States).
Highlights
Validated data on gene regulation are hard to obtain
In our case, combining information already available with information gained from the literature enabled us to further our understanding of the evolutionary history of some regulatory elements involved in pluripotency
The UCSC browser started a Wiki track system, and we hope that our effort contributes to a community effort of adding useful information to the system, so that more and more information can be viewed in context, e.g. in the context of conservation and homology information derived from sequence alignment
Summary
Information about transcription factor binding sites in regulatory regions are scattered around in the literature. This impedes their systematic in-context analysis, e.g. the inference of their conservation in evolutionary history. It became evident that the degree of conservation of gene regulatory elements had been overestimated in the past [1,2,3]. The elements can be organized into socalled modules, often termed cis-regulatory modules These are usually bound by transcription factor complexes called ‘enhanceosomes’. The typical regulatory region of a gene includes an array of cis-regulatory modules, usually consisting of sets of transcription factor binding sites (TFBS). The evolution of some regulatory elements can be traced back to the origin of the vertebrate lineage [10]
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