the genome, and of chromatin structure and gene expression, have allowed a better understanding of the general rules that underlie the differential activities of a given TF. It has emerged that chromatin structure dictates the differential binding of a given TF to cell-type-specific cis-regulatory elements. The subsequent regulation of TF activity then ensures the functional activation of only the precise subset of all regulatory sites bound by the TF that are required to mediate appropriate gene expression. Ultimately, the organization of the genome within the nucleus, and crosstalk between different cisregulatory regions involved in gene regulation, also participate in establishing a specific transcriptional program. In this Commentary, we discuss how the integration of these different and probably intimately linked regulatory mechanisms allow for TF cell-type-and context-specific modulation of gene expression.Key words: Functional genomics, Transcription factors, Cell-typespecific transcription, Chromatin, Coactivators.
Summary
Defining specificity of transcription factor regulatory activities Jérôme Eeckhoute*, Raphaël Métivier and Gilles Salbert
Journal of Cell Science
4028structure at promoters appears mostly conserved in different cell types, the presence of active chromatin marks at enhancers is mainly cell-type-specific and is biased towards enhancers that are in the vicinity of differentially expressed genes. Indeed, Heintzman and co-workers found that genes expressed in cervical carcinoma HeLa cells and leukaemia K562 cells were mostly identical, and that their promoters exhibited a similar pattern of active histone posttranslational modifications (methylation of lysine 4 and acetylation of lysine 27 of histone H3) (Heintzman et al., 2009). Conversely, these histone marks were found at distinct enhancers in the two cell types, and the distribution of enhancers that had active chromatin features was biased towards the small fraction of those genes that were differentially expressed (Heintzman et al., 2009). Accordingly, TFs that act mainly through binding to enhancers, such as steroid hormone receptors, were shown to exhibit cell-type-specific cistromes (sets of bound regions in the genome) in correlation with differential gene transcriptional regulation (John et al., 2008;Krum et al., 2008;So et al., 2007). Hence, one important function of chromatin is to determine, on a genome-wide scale, the set of regions bound by a given TF in a given cell type.Interestingly, a functional link between chromatin structure, TF recruitment and enhancer activity has been suggested to control the transcriptional regulatory activities exerted by FOXA1 and steroid hormone receptors. FOXA1 is thought to probe the chromatin and to selectively promote the binding of other TFs to regulatory regions of chromatin that were initially condensed; FOXA1 is therefore considered to be a 'pioneer factor' that allows for competency of enhancers (Cirillo et al., 2002;Sekiya et al., 2009;Zaret, 1999). Cell-type-specific FOXA1 activitie...