Insights from genomic profiling of transcription factors

Abstract

Alterations in gene expression caused by the inappropriate level, structure or function of a transcription factor have been associated with a diverse set of human diseases. However, because most human transcription factors are essentially uncharacterized, the role of transcription factors in human health is currently greatly underappreciated. Technological advances (such as chromatin immunoprecipitation followed by microarray or by sequencing) now allow transcription factor binding to be studied on a genome-wide scale. Recent discoveries, such as the finding that most transcription factors bind to thousands of places in the genome, that binding sites are not just localized to proximal promoter regions and that some binding sites lack sequences similar to the consensus motif, have stimulated new ideas concerning long-range and combinatorial regulation. Current genomic studies have not yet determined whether most human transcription factors bind alone or whether they cluster at hot spots in the genome. Answers to these questions require the genomic profiling of many more factors. A crucial unanswered question is whether all binding events have a functional outcome (perhaps under some specific condition or in a specific cell type) or whether some transcription factor–genome interactions are simply irrelevant. Issues that remain to be addressed include the design of comprehensive studies (for example, should all factors be studied in all cell types) and functional validation (for example, how can we determine the role of one specific binding site in its normal genomic context).