PMC

The concept of cellular memory. Schematic illustration highlighting the role of trxG complexes in maintaining heritable states of active gene expression in contrast to heritable silencing by PcG complexes, as defined originally for the Drosophila homeotic (Hox) gene cluster.

Regulation of Hox transcription. The boundaries of abd-A transcription and other Hox genes are established by segmentation proteins. These include the products of gap and pair-rule genes, which subdivide the embryo into 14 identical segments. During subsequent development, the “off” or “on” states of Hox transcription are maintained by the ubiquitously expressed members of the trxG of activators and the PcG of repressors via mechanisms that remain poorly understood.

trxG and PcG functions and interactions. Both trxG and PcG families include proteins that covalently modify histones and those that noncovalently modify chromatin. Covalent modifications on histones can promote or block the binding or activity of trxG complexes (e.g., SWI/SNF and KIS), PcG complexes (e.g., PRC1 and PRC2), or other factors involved in the maintenance of active or repressed states. Binding by these latter complexes has the potential to lead to further covalent modification, thus leading to iterative cycles of covalent modification and recognition of the covalent marks.

Chromosomal distribution of trxG proteins. The genome-wide distribution of trxG proteins was examined by staining Drosophila salivary gland polytene chromosomes with antibodies against BRM (A) or TRX (B). Consistent with a relatively global role in transcriptional activation, BRM is associated with hundreds of sites in a pattern that overlaps extensively with RNA Pol II. In contrast, strong TRX signals are detected at a much smaller number of sites on polytene chromosomes.

The SWI/SNF family of remodeling complexes. Each complex contains a member of SNF2/SWI2 family of ATPases and at least eight other subunits. (A) Schematic diagram of the BRM protein showing the location of the ATPase domain and carboxy-terminal bromodomain (which shows affinity to acetylated lysine residues in histone tails), which are conserved in all SNF2/SWI2 family members. SWI/SNF complexes in yeast (B), Drosophila (C), and humans (D) are shown. Drosophila trxG proteins (BRM, MOR, and OSA) and their counterparts in other organisms are shown in color. Further information about these complexes and their subunits may be found in .

Examples of developmental cell fate transformations associated with mutations in Drosophila trxG genes. (A) Wild-type first leg. The sex comb, unique to the first leg, is marked by an arrow. (B) A patch of kis mutant tissue (marked by an arrow) is partially transformed from the first leg to the second leg because of decreased Scr transcription, albeit incomplete, as evidenced by a reduction in the number of sex comb teeth. (C) A patch of mor mutant tissue (marked by an arrow) displays the partial transformation from balancer organ to wing because of decreased Ubx expression. (D) A patch of kis mutant tissue (marked by an arrow) in the fifth abdominal segment is partially transformed to a more anterior identity because of decreased Abd-B expression, as evidenced by the loss of the dark pigmentation characteristic of this segment. (A,B,D, Reprinted from .)

trxG mutations block the derepression of Hox genes in PcG mutants. (A) Leg imaginal discs stained with antibodies against the protein encoded by the Hox gene, Scr, which specifies the identity of the labial and first thoracic segments, including the first leg. (B) Basitarsal segments of the legs of wild-type and mutant adults. Note the presence of sex comb teeth on the first leg, but not the second and third legs of wild-type adults. The Scr gene is partially derepressed in the second and third leg discs, in which it is normally silent, in individuals heterozygous for mutations in PcG genes leading to the appearance of ectopic sex comb teeth on the second and third legs. These phenotypes are suppressed by mutations in brm and many other trxG genes. (A, Reprinted, with permission, from , © Elsevier; B, portion modified, with permission, from , © Elsevier.)