These authors contributed equally to this work.
Analysis of Sequence Variation Underlying Tissue-specific Transcription Factor Binding and Gene Expression
Article first published online: 18 JUN 2013
© 2013 WILEY PERIODICALS, INC.
Volume 34, Issue 8, pages 1140–1148, August 2013
How to Cite
Lower, K. M., De Gobbi, M., Hughes, J. R., Derry, C. J., Ayyub, H., Sloane-Stanley, J. A., Vernimmen, D., Garrick, D., Gibbons, R. J. and Higgs, D. R. (2013), Analysis of Sequence Variation Underlying Tissue-specific Transcription Factor Binding and Gene Expression. Hum. Mutat., 34: 1140–1148. doi: 10.1002/humu.22343
Contract grant sponsors: Medical Research Council; NIHR Biomedical Research Centre Programme; Oxford Nuffield Medical Fellowship, Oxford University.
Communicated by George P. Patrinos
- Issue published online: 15 JUL 2013
- Article first published online: 18 JUN 2013
- Accepted manuscript online: 24 APR 2013 07:49PM EST
- Manuscript Accepted: 12 APR 2013
- Manuscript Received: 18 JAN 2013
- Medical Research Council
- NIHR Biomedical Research Centre Programme
- Oxford Nuffield Medical Fellowship, Oxford University
- transcriptional regulation;
- transcription factor binding;
- allele specific
Although mutations causing monogenic disorders most frequently lie within the affected gene, sequence variation in complex disorders is more commonly found in noncoding regions. Furthermore, recent genome- wide studies have shown that common DNA sequence variants in noncoding regions are associated with “normal” variation in gene expression resulting in cell-specific and/or allele-specific differences. The mechanism by which such sequence variation causes changes in gene expression is largely unknown. We have addressed this by studying natural variation in the binding of key transcription factors (TFs) in the well-defined, purified cell system of erythropoiesis. We have shown that common polymorphisms frequently directly perturb the binding sites of key TFs, and detailed analysis shows how this causes considerable (∼10-fold) changes in expression from a single allele in a tissue-specific manner. We also show how a SNP, located at some distance from the recognized TF binding site, may affect the recruitment of a large multiprotein complex and alter the associated chromatin modification of the variant regulatory element. This study illustrates the principles by which common sequence variation may cause changes in tissue-specific gene expression, and suggests that such variation may underlie an individual's propensity to develop complex human genetic diseases.