Defining specificity of transcription factor regulatory activities

Abstract

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...

Discovering modulators of gene expression

“…Many transcription factors are shown to both activate and repress gene expression depending on sequence, chromatin structure and modulators (19,20). It is also well documented that the modulators affect a specific subset of the targets of a transcription factor (21,22), and can reverse their effect based on the target gene (23,24). Several genome-wide studies show that such complicated cases in fact might be very common (25–28).…”

Dynamic Estrogen Receptor Interactomes Control Estrogen-Responsive Trefoil Factor (TFF) Locus Cell-Specific Activities

“…A general problem that emerges from genome-wide studies is the evidence that the number of interactions made between the BSs of a transcription factor and genes promoters is not systematically reflected at the transcriptional level (74). The use of TFOs allowed us to provide further indications on how binding sites for a transcription factor are mobilized in space and time in order to regulate the transcription of its target genes.…”

DLX1 acts as a crucial target of FOXM1 to promote ovarian cancer aggressiveness by enhancing TGF-β/SMAD4 signaling

“…Moreover, the availability of co-factors or cellular stimulators, such as estrogen, in different cellular contexts in different tumor developing stages may also affect the binding sites for the same transcription factor. 42 Therefore, our study found three out of 18 putative genes could be remarkably upregulated by enforced expression of FOXM1. Further biochemical and functional analyses revealed that DLX1 is a direct target of FOXM1 in mediating cell migration/invasion of high-grade serous ovarian cancer cells.…”

“…41 This difference in the FOXM1-binding sites may be due to a cell type- and context-specific sequences. 42 For example, a recent study used MCF7 breast cancer cells to investigate FOXM1-binding, while we used ovarian cancer cells in this study. Moreover, the availability of co-factors or cellular stimulators, such as estrogen, in different cellular contexts in different tumor developing stages may also affect the binding sites for the same transcription factor.…”