A Review of Composite Elements

Composite regulatory elements contain two or more closely situated binding sites for distinct transcription factors and provide a way for crosstalk between different regulatory pathways. The term "composite element" was introduced during studies of the glucocorticoid response element in the mouse proliferin promoter, where the glucocorticoid receptor transcription factor binding site was found to be adjacent to an AP-1 site (Diamond et al., 1990). This term was later applied to different pairs of interacting transcription factor binding sites and transcription 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 which both protein-DNA and protein-protein interactions contribute to a highly specific pattern of transcriptional regulation (Kel et al., 1995b; Kel et al., 1997).

Composite elements can be classified based on the following criteria:

characteristics of interactions between the transcription factors involved (either synergism or antagonism)
structure of transcription factors (structure of DNA-binding domains, for example)
function provided by the composite element (tissue-specificity or inducibility, for example)

These criteria are described in greater detail below.

Classifying Composite Elements Based on Interactions Between Transcription Factors

Interactions between the transcription factors that comprise a composite element can be synergistic or antagonistic. Descriptions of synergistic and antagonist composite elements are provided below.

Synergistic Composite Elements

In synergistic composite elements, simultaneous interactions of two transcription factors with closely situated target sites results in a high level of a transcriptional activation, beyond an additive effect. Many examples of cooperative binding of transcription factors to DNA, leading to the formation of ternary protein-protein-DNA complexes, have been described in the scientific literature (Moreno et al., 1995; Brass et al., 1996; Linhoff et al., 1997; Muhlethaler-Mottet et al., 1998; Butscher et al., 1998, and others). A result of these protein-protein interactions is the formation of a new protein surface that is common for the transcription factor pair. The interaction between two transcription factors may be direct (Brass et al., 1996; Chen et al., 1998, and others), or it may be mediated by a co-activator such as p300/CREB-BP (Butscher et al., 1998).

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

A number of transcription 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 the assembly of nucleosome-like structures (Linhoff et al., 1997). Some factors bind primarily to DNA and may serve as gathering centers due to sequence similarity with histone-fold motif, as is the case of the subunits of NF-Y factor (Linhoff et al., 1997).

Antagonistic Composite Elements

Within an antagonistic composite elements, two transcription 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 may mask an activation domain of an activator (Diamond et al., 1990). A number of molecular mechanisms are suggested for functioning of both synergistic and antagonistic composite elements (Kel et al., 1997).

Classifying Composite Elements Based on Transcription Factor Structure

We applied an existing transcription factor classification system (Wingender, 1997) to classify composite elements in terms of a transcription factor's DNA binding domains. The transcription factors interacting at in an individual composite element typically belong to different classes. Transcription factors of bZIP, REL and ETS classes play an important role in composite elements, and about fifty percent of all known composite elements contain at least one binding site for these proteins. In general, transcription factors ofbZIP, REL and ETS classes can be characterized as inducible by various extracellular stimuli.

Classifying Composite Elements Based on Function

Functional properties and tissue distribution of transcription factors can vary significantly within the same class of factors. Based on this, we applied another criterion for classifying composite elements that takes into account the specific function provided by the composite element (Kel et al., 1997). Cross-coupling between structurally and functionally different transcription factors on composite regulatory elements seems to be a general regulatory pathway. In fact, it opens up a broad possibility for coding very specific gene expression profiles in the structure of gene regulatory regions.

Composite elements can be divided into several functional groups:

Composite elements formed by binding sites for two inducible transcription factors. These composite elements enable crosstalk between signal transduction pathways.
Composite elements formed by binding sites for a tissue-enriched transcription factor and an inducible transcription factor. These composite elements provide tissue-specific responses to inducing signals.
Composite elements formed by binding sites for a tissue-enriched trancription factor and a ubiquitous transcription factor. These composite elements provide some additional features of the tissue-specific transcriptional regulation.
Composite elements formed by binding sites for an inducible transcription factor and a ubiquitous transcription factor. These composite elements provide some additional features of the inducible transcriptional regulation.
Composite elements formed by binding sites for two tissue-enriched transcription factors. These composite elements provide some particular aspects of tissue-specific regulation.

Classification of Composite Elements in TRANSCompel

TRANSCompel composite elements have been classified based on their function. Details about this classification are provided here. Details about how the functions of composite elements were analyzed are provided here.

References

Brass AL, Kehrli E, Eisenbeis CF, Storb U, Singh H. (1996) Pip, a lymphoid-restricted IRF, contains a regulatory domain that is important for autoinhibition and ternary complex formation with Ets factor PU.1. Genes Dev 10:2335-2347.

Butscher WG, Powers C, Olive M, Vinson C, Gardner K. (1998) Coordinate transactivation of the interleukin-2 CD28 response element by c-Rel and ATF-1/CREB2. J Biol Chem 273:552-560.

Cantwell C A, Sterneck E, Johnson PF. (1998) Interleukin-6-specific activation of the C/EBPdelta gene in hepatocytes is mediated by Stat3 and Sp1. Mol Cell Biol 18:2108-2117.

Casolaro V, Georas SN, Song Z, Zubkoff ID, Abdulkadir SA, Thanos D, Ono SJ. (1995) Inhibition of NF-AT-dependent transcription by NF-kappaB: implications for differential gene expression in T helper cell subsets. Proc Natl Acad Sci USA 92:11623-11627.

Chen L, Glover JNM, Hogan PG, Rao A, Harrison SC. (1998) Structure of the DNA-binding domains from NFAT, Fos and Jun bound specifically to DNA. Nature 392:42-48.

Diamond MI, Miner JN, Yoshinaga SK, Yamamoto KR (1990) Transcription factor interactions: selectors of positive or negative regulation from a single DNA element. Science 249:1266-1272.

Du W, Thanos D, Maniatis T. (1993) Mechanism of transcriptional synergism between distinct virus-inducible enhancer elements. Cell 74:887-898.

Gutman A, Wasylyk B. (1990) The collagenase gene promoter contains a TPA and oncogen responsive unit encompassing the PEA3 and AP-1 binding sites. EMBO J 9:2241-2246.

Heinemeyer T, Wingender E, Reuter I, Hermjakob H, Kel AE, Kel OV, Ignatieva EV, Ananko EA, Podkolodnaya OA, Kolpakov FA, Podkolodny NL, Kolchanov NA. (1998) Databases on transcription regulation: TRANSFAC, TRRD and TRANSCompel. Nucleic Acids Res 26:362-367.

Jackson DA, Rowader KE, Stevens KY, Jiang C, Milos P, Zaret KS. (1993) Modulation of liver-specific transcription by interaction between Hepatocyte Nuclear Factor 3 and Nuclear Factor 1 binding DNA in close apposition. Mol Cell Biol 13:2401-2410.

Karas H, Kel AE, Kel OV, Kolchanov NA, Wingender E. (1997) Integrating the knowledge on gene regulation. Mol Biol (Mosk) 31:531-539.

Kel AE, Kolchanov NA, Kel OV, Romashencko AG, Ananko EA, Ignatieva EV, Merkulova TI, Podkolodnaya OA, Stepanenko IL, Kochetov AV, Kolpakov FA, Podkolodnyi NL, Naumochkin AN. (1997) TRRD: Database on Transcription Regulatory Regions of Eukaryotic Genes. Mol Biol (Mosk) 31:626-636.

Kel A, Kel-Margoulis O, Babenko V, Wingender E. Recognition of NFATp/AP-1 composite elements within genes induced upon the activation of immune cells. J Mol Biol 288:353-376.

Kel OV, Romaschenko AG, Kel AE, Naumochkin AN, Kolchanov NA. (1995a) Data representation in the TRRD - a database of transcription regulatory regions of the eukaryotic genomes. Proceedings of the 28th Annual Hawaii International Conference on System Scienses [HICSS]. Biotechnology Computing, IEE Computer Society Press, Los Alamitos, CA, 5:42 -51.

Kel OV, Romaschenko AG, Kel AE, Wingender E, Kolchanov NA. (1995b) A compilation of composite regulatory elements affecting gene transcription in vertebrates. Nucleic Acids Res 23:4097-4103.

Kel OV, Romaschenko AG, Kel AE, Wingender E, Kolchanov NA. (1997) Composite regulatory elements: classification and description in the TRANSCompel database. Mol Biol (Mosk) 31:498-512.

Kerppola TK, Curran T. (1991) Fos-Jun heterodimers and Jun homodimers bend DNA in opposite orientations: implications for transcription factor cooperativity. Cell 66:317-326.

Klein-Hessling S, Schneider G, Heinfling A, Chuvpilo S, Serfling E. (1996) HMG I(Y) interferes with the DNA binding of NF-AT factors and the induction of the interleukin 4 promoter in T cells. Proc Natl Acad Sci USA 93:15311-15316.

Kolchanov NA, Ananko EA, Podkolodnaya OA, Ignatieva EV, Stepanenko IL, Kel-Margoulis OV, Kel AE, Merkulova TI, Goryachkovskaya TN, Busigina TN, Kolpakov FA, Podkolodny NL, Naumochkin AN, Romashchenko AG (1999) Transcription regulatory regions database (TRRD): its status in 1999. Nucleic Acids Res 27:303-306.

Linhoff MW, Wright KL, Ting JPY. (1997) CCAAT-binding factor NF-Y and RFX are required for in vivo assembly of a nucleoprotein complex that spans 250 base pairs: the invariant chain promoter as a model. Mol Cell Biol 17:4589-4596.

Moreno CS, Emery P, West JE, Durand B, Reith W, Mach B, Boss M. (1995) Purified X2 binding protein (X2BP) cooperatively binds the class II MHC X box region in the presence of purified RFX, the X box factor deficient in the Bare Lymphocyte Syndrom. J Immunol 155:4313-4321.

Moulton KS, Semple K, Wu H, Glass CK (1994) Cell-specific expression of the macrophage scavenger receptor gene is dependent on PU.1 and composite AP-1/ets motif. Mol Cell Biol 14:4408-4418.

Muhlethaler-Mottet A, Berardino WD, Otten LA, Mach B. (1998) Activation of the MHC Class II Transactivator CIITA by interferon-gamma requires cooperative interaction between Stat1 and USF-1. Immunity 8:157-166.

Ohmori Y, Schreiber RD, Hamilton TA. (1997) Synergy between interferon-gamma and tumor necrosis factor alpha in transcriptional activation is mediated by cooperation between Signal Transducer and Activator of Transcription 1 and Nuclear Factor kappaB. J Biol Chem 272:14899-14907.

Quandt K, Frech K, Karas H, Wingender E, Werner T. (1995) New fast and versatile tools for detection of consensus matches in nucleotide sequence data. Nucleic Acids Res:23, 4878-4884.

Perier RC, Junier TH, Bucher P. (1998) The Eukaryotic Promoter Database EPD. Nucleic Acids Res 26: 53-357.

Rao A, Luo C, Hogan PG. (1997) Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol 15:707-747.

Rooney JW, Sun YL, Glimcher LH, Hoey T. (1995) Novel NFAT sites that mediate activation of the interleukin-2 promoter in response to T-cell receptor stimulation. Mol Cell Biol 15:6299-6310.

Stros M, Stokrova J, O'Thomas J. (1994) DNA looping by the HMG-box domains of HMG1 and modulation of DNA binding by the acidic C-terminal domain. Nucleic Acids Res 22:1044-1051.

Takeuchi A, Reddy GS, Kobayashi T, Okano T, Park J, Sharma, S. (1998) Nuclear Factor of Activated T cells (NFAT) as a molecular target for 1alpha,25-dihydroxyvitamin D3-mediated effects. J Immunol 160:209-218.

Wingender E. (1997) Classification scheme of eukaryotic transcription factors. Mol Biol (Mosk) 31:483-497.

Wingender E, Kel AE, Kel OV, Karas H, Heinemeyer T, Dietze P, Knüppel R, Romaschenko AG, Kolchanov NA. (1997) TRANSFAC, TRRD and TRANSCompel: Towards a federated database system on transcriptional regulation. Nucleic Acids Res 25:265-268.

Zaiman AL, Lenz J. (1996) Transcriptional activation of a retrovirus enhancer by CBF (AML1) requires a second factor: evidence for cooperativity with c-Myb. J Virol 8:5618-5629.