BIOLOGICAL OVERVIEW

SWI-SNF is a chromatin remodeling protein complex implicated in yeast and mammals in the modification of the association of DNA with histones, an important aspect in gene activation. Moira (Mor) joins Brahma and Snf5-related 1, two other known SWI-SNF subunits that also act as positive regulators of the homeotic genes (Crosby, 1999), and moira is required for the function of multiple homeotic genes of the Antennapedia and bithorax complexes (HOM genes) in most imaginal tissues (Brizuela, 1997). moira encodes a homolog of human and yeast chromatin-remodeling factors BAF170, BAF155 and SWI3 and is a member of the trithorax group of homeotic gene regulators in Drosophila (Crosby, 1999).

mor was originally identified in a screen for mutations that act as dominant suppressors and/or enhancers of homoeotic alleles of the Polycomb and/or Antennapedia loci. mor causes suppression of Pc mutant phenotypes (Kennison, 1998). Heterozygous mor mutations suppress the following Polycomb-induced phenotypes:

1. Derepression of the Antp gene in the eye-antennal disc causes replacement of adult antennal structures with leg structures.
2. Derepression of the Sex combs reduced gene in the second and third leg discs causes the appearance of first leg structures in the second and third legs of the adults.
3. Derepression of the Ultrabithorax gene in the wing discs causes the appearance of haltere tissue in the adult wing.
4. Derepression of the genes in the BXC (abdominal-A and Abdominal-B) causes cells of the fourth abdominal segment of the adult to differentiate structures of a more posterior identity.

moira mutations suppress the derepression phenotypes caused by mutations in another Pc group gene, Polycomblike. moira mutant clones in the haltere differentiate large bristles, characteristic of the anterior wing margin, and often lead to absence or duplication of halteres. Homozygous mor mutations in the posterior wing result in a distorted wing shape; the venation is disrupted and large socketed bristles appear along the posterior wing margin. Clones in the leg result in the femur and tibia being short and twisted and enlargement of the tarsal segment. Clones in the head cause the shape of the head to be abnormal in the dorsal region and sometimes cause the ocellus to be abnormal or absent. Embryos homozygous for moira mutations have defects in head structures, including truncated lateralgraten and defects in the mouth hooks and dorsal bridge. The first and second midgut constrictions are shifted to the posterior, when compared to their wild-type positions (Brizuela, 1997).

The head defects are thought to result from failure to properly express the homeotic gene Deformed (Harding, 1995). Imaginal disc staining for Sexcombs reduced protein in a mor and polycomb genetic background (Pattatucci, 1991) showed that Pc induced ectopic Scr protein expression in second and third leg imaginal discs is reduced by the mor mutation. Thus mor is a positive regulator of Scr expression.

The requirement for moira function is at the level of transcription. The ability of moira mutations to suppress Antp homeotic phenotypes is dependent on the Antp promoter. moira is also required for transcription of the engrailed segmentation gene in the imaginal wing disc. Because homozygous mor clones have phenotypes similar to those seen in clones of cells that have lost en function, en transcription was examined in clones of cells in the posterior wing. In the absence of transcriptional activation by mor, the pattern of en is altered. Greatly reduced en expression is found in wing clones. The abnormalities caused by the loss of moira function in germ cells suggest that at least one other target gene requires moira for normal oogenesis (Brizuela, 1997).

It is the biochemical sequence of Mor as well as its physical interaction with Brahma, that identifies Mor as the Swi3 component of the Brahma complex (Crosby, 1999). For more information about the transcriptional role of the Brahma complex, see Brahma. What exactly is the role of Swi3 within the Brahma complex? A clue from mammals comes from a study that searched for interacting partners of Cyclin E (Shanahan, 1999 (see Drosophila Cyclin E). BAF155, a component of the mammalian SWI-SNF complex has been identified as a Cyclin E interacting protein. Likewise, BRG1 and hBR M, two mammalian Brahma homologs, and Ini1-hSNF5, a homolog of Drosophila Snf5-related 1, also interact with Cyclin E. BRG1 was shown to facilitate the interaction of GAF155 with cyclin E, as reduced cellular levels of BRG1 result in reduced levels of BAF155 found complexed with cyclin E, and restoration of high levels of BRG1 increases the level of cyclin E-BAF155 complexes. BRG1 overexpression induces cell cycle arrest in cultured cells; coexpression of cyclin E with BRG prevents growth arrest. In the process, Cyclin E reverses a flattened-cell morphology induced by BRG1. Both BAF155 and BRG1 contain cdk consensus phosphorylation sites, and both can be phosphorylated by cyclin-cdk2-associated kinase activity in vitro. BRG1 and BAF155 are in a phosphorylated form in the cyclin E complex.

A recent report by Sif (1998) has demonstrated that the mitotic inactivation of the human SWI-SNF complex is caused by phosphorylation of various SWI-SNF subunits, including BRG1 and hSWI3. The identity of the kinases responsible for these regulatory phosphorylations remains unknown. These results, along with the demonstrated association of SWI3 with cyclin E (Shanahan, 1999), suggest that the SWI/SNF apparatus may be modulated both positively and negatively throught the cell cycle. While mitotic phosphorylation of BRG1 and SWI3 may be required for chromatin-mediated transcriptional repression during mitosis, phosphorylation on different sites may be required for chromatin remodeling during G1 as cells prepare for DNA synthesis (Shanahan, 1999).

GENE STRUCTURE

PROTEIN STRUCTURE

Amino Acids - 1189

Structural Domains

mor encodes a fruit fly homolog of the human and yeast chromatin-remodeling factors BAF170, BAF155, and SWI3. The degree of overall identity between Mor and BAF170 is marginally higher than between Mor and human BAF155. The Mor protein is as identical to the mouse SWI3 homolog, SRG3, as it is to BAF155. A lower level of overall identity is exhibited to SWI3 itself (37% identity and 47% similarity). Alignment of the Mor sequence with those of BAF170, BAF155, SRG3 and SWI3 reveals that Mor contains all three of the conserved regions previously described in these proteins and that the level of sequence identity between Mor and the others is highest in these regions. Mor is most similar to the other proteins (especially BAF170) in region I, which is rich in prolines as well as hydrophobic and aromatic amino acids, leading to the suggestion that it may be hidden within the SWI-SNF complex. Region II is a tryptophan-rich domain that has been termed the SANT domain because it is present in four proteins (SWI3, ADA2, N-CoR, and TFIIB) that participate in basal or activated transcription. Region III contains a leucine zipper oligomerization motif, suggesting that Mor may be able to bind to itself or another leucine zipper-containing protein. In addition to these conserved domains, the C-terminus of Mor is like that found in BAF170, BAF155 and SRG3: very proline rich, but more glutamine rich than the corresponding termini in these proteins. The leucine zipper motif of MOR is likely to participate in self-oligomerization; the equally conserved SANT domain, with no known function, may be required for optimal binding to BRM (Crosby, 1999).

date revised: 13 April 98

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