TRANSCompel™ - Documentation

Composite regulatory elements: structure, function and classification.

Composite regulatory elements contain two closely situated binding sites for distinct transcription factors, and actually are minimal functional units providing combinatorial transcriptional regulation.

The term "composite element" was introduced while studying glucocorticoid response element in the mouse proliferin promoter where glucocorticoid receptor binding site is adjacent to an AP-1 site (Diamond et al., 1990). Further, this term was applied to quite different pairs of interacting sites and factors (Gutman and Wasylyk, 1990; Jackson et al., 1993; Du et al., 1993; Moulton et al., 1994; Rooney et al., 1995, Brass et al., 1996, Klein-Hessling et al., 1996; Butscher et al., 1998, and others). Based on the known examples we define a composite element as a minimal functional unit within that both protein-DNA and protein-protein interactions contribute to a highly specific pattern of gene transcriptional regulation (Kel,O.V. et al., 1995b; Kel,O.V. et al., 1997).

Composite elements can be classified on the base of different criteria:

1. Character of interactions between transcription factors involved (synergism or antagonism)
2. Structure of transcription factors, namely structure of DNA-binding domains
3. Combinatorial regulation provided by a composite element.

There are two main types of composite elements: synergistic and antagonistic ones.

In synergistic CEs simultaneous interactions of two factors with closely situated target sites result in a non-additively high level of a transcriptional activation. Highly cooperative binding of factors to DNA and formation of a ternary complex protein-protein-DNA was experimentally shown in many cases (Moreno et al., 1995; Brass et al., 1996; Linhoff et al., 1997; Muhlethaler-Mottet et al., 1998; Butscher et al., 1998, and others). As a result of protein-protein interactions a new protein surface may be formed which is common for factor pair.

Interaction between two factors may be direct (Brass et al., 1996; Chen et al., 1998, and others), or mediated by coactivator, for instanse by p300/CREB-BP (Butscher et al., 1998).

In some cases two factors independently binding to DNA, still synergistically activate transcription (Zaiman and Lenz, 1996; Ohmori et al., 1997; Cantwell et al., 1998). In this case synergistic effect may be accounted for by simultaneous interactions of activation domains of two factors with different components of the basal transcription complex, and/or direct factor-factor interections may elicit conformational changes in activation domains.

A number of factors are known to bend DNA and thus permit binding of other factors (Stros et al., 1994; Kerppola and Curran, 1991).

Hierarchy of transcription factor loading may occur due to assembling of nucleosome-like structures (Linhoff et al., 1997). Some factors bind primarily to DNA and may serve as a gathering centers due to sequence similarity with histone-fold motif as in case of the subunits of NF-Y factor (Linhoff et al., 1997).

Within an antagonistic CE two factors interfere with each other.

In some cases competition for overlapping sites leads to a mutually exclusive binding (Casolaro et al., 1995; Klein-Hessling et al., 1996; Takeuchi et al., 1998, and others).

In other cases, factors can bind to DNA simultaneously, but binding of a repressing factor possibly “masks” an activation domain of an activator (Diamond et al., 1990).

A number of molecular mechanisms are suggested for functioning of both synergistic and antagonistic CEs (Kel,O.V. et al., 1997).

To classify composite elements in terms of factors’ DNA-binding domains we applied a previously developed transcription factor classification (Wingender, 1997). The factors interacting at an individual CE mostly belong to different classes. Transcription factors of bZIP, REL and ETS classes play a very important role in composite elements and about 50% of known CEs contain at least one binding site for these proteins. In general, transcription factors of these three classes can be characterized as factors inducible by various extracellular stimulus. Examples of the most frequent structural types of composite elements collected in TRANSCompel are given in Table 1. They include 26 composite elements of bZIP/REL type, 13 CEs of bZIP/ETS type, 6 elements of REL/HMG type, 5 CEs of ETS/RUNT, and 3 CEs of ETS/MADS type. Structurally similar elements are present in several different genes, which apparently implies that such regulatory modules are functionally significant.

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