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First published online December 21, 2006
doi: 10.1242/10.1242/dev.02723

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Polycomb/Trithorax response elements and epigenetic memory of cell identity

¹ IMBA - Institute of Molecular Biotechnology GmbH, Dr Bohr-Gasse 3, 1030 Vienna, Austria.
² ZMBH - Zentrum für Molekulare Biologie der Universität Heidelberg, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.

View larger version (8K): [in this window] [in a new window]   Fig. 1. Polycomb and Trithorax in stem cells and differentiated cells. (A) Stem cells have a high capacity to proliferate and to generate different differentiated cell types, and following division can give rise to a new stem cell and a differentiated daughter cell. (B) Classes of genes that must be active or silenced in stem cells and differentiated cells are shown. (Left) Tumor suppressors and genes specifying cell fate are silenced in stem cells, whilst genes conferring `stemness' are active. (Right) The activities of tumor suppressors and `stemness' genes are reversed in differentiated cells, which have limited proliferation capacity. Most genes that specify different cell fates continue to be silenced in differentiated cells, except for those that are required to specify a given fate. The PcG proteins target many genes of the three classes shown and are essential in stem cells and differentiated cells, both for the maintenance of silent or active states and for the switching of these states upon differentiation (see main text for details).

View larger version (11K): [in this window] [in a new window]   Fig. 2. Overlap between Polycomb targets in three different studies. A comparison of results from three studies which looked at binding profiles for several PcG proteins using tiling path arrays covering all or part of the Drosophila genome (Negre et al., 2006; Tollhuis et al., 2006; Schwartz et al., 2006) (see Box 1 for more detail on the techniques used). The diagram compares the regions in common between the three studies (2 Mb of the X chromosome and 3 Mb of chromosome 2L.) The large-type numbers in each field show the number of genes found to be bound by PcG proteins. Subscript numbers in brackets show the number of those genes that have a score of over 70 using PRE/TRE prediction (Ringrose et al., 2003). The score cut-off used in Ringrose et al. (Ringrose et al., 2003) was 157 (see main text for details).

View larger version (20K): [in this window] [in a new window]   Fig. 3. PRE/TRE motifs and flexibility of PRE/TRE design. (A) DNA motifs shown to be important for PRE/TRE function. The Grh (Grainy head) protein binds to several different PRE/TRE sites. The motif shown is that found in PRE/TREs by Blastyak et al. (Blastyak et al., 2006). The Dsp1 protein also has broad DNA-binding specificity (Brickman et al., 1999). The motif shown is that used by Dejardin et al. (Dejardin et al., 2005). Gaf binds the same target sequence as Pipsqueak (Psq), suggesting that the two proteins may compete or cooperate at closely spaced sites. (B) Many of these motifs are important for regulating genes that do not have PRE/TREs, for example the Drosophila white gene which is regulated by the Zeste protein (600 bp of upstream regulatory region are shown). These motifs are also short and occur randomly in DNA, such as in the bacterial LacZ gene (the first 600 bp of the coding sequence are shown). (C) PRE/TREs have different combinations of motifs, with no preferred order or number. Shown here are 600 bp of the bxd and Fab-7 PREs from the Drosophila Bithorax complex, and of PRE/TREs from the Drosophila engrailed (en), vestigial (vg) and homothorax (hth) loci. Grey boxes show minimal PRE/TREs where these have been defined (Dejardin et al., 2005; Brown et al., 2005). Flanking sequences contain additional motif clusters which may contribute to the function of these PRE/TREs in their endogenous context.

View larger version (28K): [in this window] [in a new window]   Fig. 4. Model of epigenetic memory at PRE/TREs during the cell cycle. A model based on published findings (Buchenau et al., 1998; Schmitt et al., 2005; Sanchez-Elsner et al., 2006). (1) During interphase, PRE/TREs silence by default. Only those PRE/TREs that are transcribed escape this silencing. (2,3) After replication, transcription through the PRE/TRE continues to counteract silencing. (4) At the onset of mitosis, the PcG proteins PSC, PH and PC (Posterior sex combs, Polyhomeotic and Polycomb, respectively) dissociate simultaneously from chromatin (Buchenau et al., 1998). (5) During mitosis, there is a global shutdown of transcription. Those PRE/TREs that were transcribed in the previous interphase must somehow be marked. (6) The PcG proteins reassociate with chromatin at different points during late mitosis. PSC returns during anaphase, PH in telophase and PC at the beginning of interphase (Buchenau et al., 1998). The transcription of marked PRE/TREs must resume before a functional PcG complex has assembled at PRE/TREs. This would prevent default silencing in the next interphase.

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