Me Me

Me Me

Me Me

Fig. 9.3 Repression by chromatin-remodeling factors. (A)

Levels of histone acetylation are reduced by HDACs (crossed "Ac"), while levels of histone methylation (Me) are increased by histone methyl transferases. DNA can be methylated by DNA methyltransferases (indicated by a zig-zag). These modifications change the chromatin structure, possibly preventing activators from binding DNA. (B) Repression mediated by Polycomb group proteins (PcG). The PcG complex represses transcription by either spreading to cover DNA (C) or inhibiting the promoter activity via a looping mechanism (D).

F: Role of Multiple Repression Domains

It is known that repressors often have multiple repression domains. These domains function qualitatively and/or quantitatively different, or act in a tissue/cell-type specific manner.

Two evolutionarily conserved repression domains of Kr├╝ppel have been characterized using Drosophila S2 cells, non Drosophila cell lines CV-1 and U20S, and Drosophila transgenic embryos (Hanna-Rose et al., 1997; Licht et al., 1994; Nibu et al., 2003; Nibu et al., 1998a; Nibu et al., 2001; Sauer et al., 1995). The C-terminal repression domain (402-502aa), which is dCtBP-dependent in vivo and TFIIbeta-dependent in vitro, can function in all of the cell types tested. On the other hand, the N-terminal repression domain (62-92aa) is active in transfected CV-1 cells (Hanna-Rose et al., 1997; Licht et al., 1994), but is dispensable in the Drosophila blastoderm embryo (Nibu et al., 2003), suggesting a tissue/cell-type specific role.

Two repression domains of Knirps, one dCtBP-

dependent and the other dCtBP-independent domains, function in transgenic embryos and in S2 cells (Keller et al., 2000; Struffi et al., 2004). In dCtBP mutant embryos, expression of eve stripes 4/6 is derepressed due to the loss of Knirps-mediated repression, but Knirps continues to repress the eve stripes 3/7 enhancer. In contrast, the mutant form of Knirps lacking the dCtBP-dependent repression domain is able to repress not only the eve stripes 3/7 enhancer but also the eve stripes 4/6 enhancer in a concentration-dependent manner. These results indicate that the two domains contribute to the full repression activity of Knirps quantitatively rather than qualitatively.

Brinker is known to interact with both Groucho and dCtBP. Brinker carries at least three repression domains, a dCtBP interacting domain, a Groucho interacting domain, and a newly identified region called 3R (Hasson et al., 2001; Winter and Campbell, 2004). These domains enable to repress different target genes, both quantitatively and qualitatively.

G: Molecular Switches: Interchanging Coactivators and Corepressors

Some DNA-binding transcription factors responding to signaling pathways play dual roles in transcription (Barolo and Posakony, 2002). They can become either activators or repressors by interchanging coactivators and corepressors in response to signals.

When cells are stimulated by the Wnt ligand through Frizzled receptors, beta-Catenin (Armadillo) is activated and translocated into the nucleus, where it serves as a coactivator for a DNA-binding factor TCF (Pangolin) to induce its target genes (Roose and Clevers, 1999). In cells lacking a Wnt signal, however, TCF keeps its target genes off by recruiting Groucho (Cavallo et al., 1998). In addition, Drosophila CBP acetylates a lysine residue in the beta-Catenin binding domain of TCF and this modification dissociates beta-Catenin from TCF, resulting in repression (Waltzer and Bienz, 1998).

Similarly, a Drosophila DNA-binding factor Su(H) acts as an activator by recruiting coactivators in the presence of Notch signaling (Lai, 2002). In contrast, binding of Hairless, Groucho, and dCtBP convert Su(H) into a repressor that inhibits its target genes in unstimulated cells (Barolo et al., 2002).

Finally, nuclear hormone receptors that sequence-specifically bind DNA can change their roles in transcription (Baek and Rosenfeld, 2004; Glass and Rosenfeld, 2000). In the absence of ligands, a heterodimer containing TR and retinoic acid receptor (TR/RXR) bound to its binding site interacts with the N-CoR

corepressor and with two other corepressors, Sin3A and HDAC1 (Heinzel et al., 1997; Horlein et al., 1995). However, ligand binding alters the conformation of the receptors and this conformational change allows TR to switch its interacting factors from these corepressors to the coactivators containing SRC-1, PCAF, and CBP. These histone acetylases and histones deacetylase ultimately define the fate of transcription.

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