TBP-like Factors Come into Focus

The papers by Dantonel et al. 2000xDantonel, J.-C, Quintin, S, Lakatos, L, Labouesse, M, and Tora, L. Mol. Cell. 2000; 6: 715–722Abstract | Full Text | Full Text PDF | PubMedSee all ReferencesDantonel et al. 2000 and Kaltenbach et al. 2000xKaltenbach, L, Horner, M.A, Rothman, J.H, and Mango, S.E. Mol. Cell. 2000; 6: 705–713Abstract | Full Text | Full Text PDF | PubMedSee all ReferencesKaltenbach et al. 2000 demonstrate that TLF is an essential transcription factor required for transcription of a restricted set of specific genes in the early C. elegans embryo. One or more of these TLF-dependent genes is required for the viability of embryonic cells and the differentiation of virtually all cell lineages. Now that it is clear that TLF is essential for cellular differentiation, a number of significant questions arise. What genes transcribed during embryogenesis besides pes-10 are direct targets of TLF? How do they contribute to differentiation? Are end-1 and other key transcription factors that act as developmental regulators for all the cell lineages in the early embryo direct TLF targets? Since TLF is expressed ubiquitously throughout the life cycles of metazoans, what genes does it control in differentiated cells? The answer to this question will likely require the isolation of conditional mutants of TLF, such as temperature-sensitive mutants, to allow the inactivation of TLF once early stages in embryogenesis are complete.Another interesting question concerns how TLF functions in transcription. Since TLF is closely related to TBP and can bind TFIIA and TFIIB in vitro (10xMoore, P.A, Ozer, J, Salunek, M, Jan, G, Zerby, D, Campbell, S, and Lieberman, P.M. Mol. Cell. Biol. 1999; 19: 7610–7620PubMedSee all References, 14xRabenstein, M.D, Zhou, S, Lis, J.T, and Tjian, R. Proc. Natl. Acad. Sci. USA. 1999; 96: 4791–4796Crossref | PubMed | Scopus (123)See all References, 17xTeichmann, M, Wang, Z, Martinez, E, Tjernberg, A, Zhang, D, Vollmer, F, Chait, B.T, and Roeder, R.G. Proc. Natl. Acad. Sci. USA. 1999; 96: 13720–13725Crossref | PubMed | Scopus (88)See all References) an obvious model is that TLF replaces TBP in the assembly of general transcription factors and RNA polymerase II into a transcription preinitiation complex on TLF-dependent promoters. Since TLF does not bind to TATA boxes, the simplest version of this model predicts that TLF-dependent promoters would have a TLF binding site in place of a TATA box near the transcription start site. However, the one promoter to which TLF has been shown to bind in vivo, the pes-10 promoter, does have a potential TATA box close to the transcription start site, although end-1, another TLF-dependent gene, does not (Kaltenbach et al. 2000xKaltenbach, L, Horner, M.A, Rothman, J.H, and Mango, S.E. Mol. Cell. 2000; 6: 705–713Abstract | Full Text | Full Text PDF | PubMedSee all ReferencesKaltenbach et al. 2000). At present, there is no data to indicate whether TLF functions in the absence of TBP or in conjunction with TBP. It is even possible that TLF functions similarly to other regulatory transcription factors with distinct DNA binding and activation domains, but with a DNA binding domain similar to the TBP core and assisted by TFIIA and TFIIB. However, this seems unlikely given the close similarity of TLFs and TBPs. In addressing this question, it would be interesting to determine the TLF binding site(s) in the pes-10 300 bp promoter fragment studied by Kaltenbach et al. and in other direct targets of TLF. Are they within a few tens of base pairs of the transcription start sites? If insertions or deletions of several base pairs were made between a TLF binding site and the transcription start site, would the start site shift accordingly, as in the classic experiments that established that TATA boxes determine transcription start sites?It is remarkable that TLFs have been found in multicellular animals, but not in fungi or plants. It has been suggested that TBP-like factors might function like sigma factors in bacteria that direct RNA polymerase to specific classes of genes. However, so far, genomic sequencing has revealed only two TBP-like factors in most metazoans (except Drosophila), rather than the five to ten sigma factors in a single species of bacteria. If TBP-like factors function as sigma factors do in bacteria, it would seem that there should be more TBP-like factors in multicellular animals, and that they would be found in fungi and plants as well as metazoans. Rather, it seems that TLF evolved early in metazoans, probably from a duplication of a TBP gene, to perform some function that cannot be accomplished by TBP and is required for cellular differentiation. It will be of considerable interest to learn more precisely what that function is.*E-mail: berk@mbi.ucla.edu