The goal of the Section on Drosophila Gene Regulation
is to understand the regulation of homeotic gene function in Drosophila
. The homeotic genes specify segmental identities in Drosophila
at both the embryonic and adult stages. They encode homeodomain-containing
transcription factors that control cell fates by regulating the transcription
of down-stream target genes. The homeotic genes are expressed in precise
spatial patterns that are crucial for the proper determination of segmental
identities. Both loss of expression and ectopic expression in the wrong
tissues lead to changes in segmental identities. These changes in identity
provide a powerful assay to identify the trans-acting factors that
regulate the homeotic genes and the cis-acting sequences through
which they act. Both the homeotic genes and the trans-acting factors
that regulate them are conserved between Drosophila and man. In
addition to many conserved developmental genes, at least half of the disease-
and cancer-causing genes in man are conserved in Drosophila , making
Drosophila a very important model system for the study of human
development and disease.
Transcriptional Activators of Homeotic Genes
Kennison, Green, Cooper in collaboration with M. Vázquez, Cuernavaca,
Mexico
Genetic studies have identified the trithorax group of genes that
are required for expression or function of the homeotic genes. Reduced
function of the trithorax group of genes mimics loss of function
of the homeotic genes. Many of the trithorax group of genes have
been shown to be required for the maintenance of transcription of the
homeotic genes during development. Our laboratory has identified at least
two dozen trithorax group genes, most of which were previously
unknown. Two of the genes (skuld and kohtalo) encode subunits
of the mediator coactivator complex. This complex is highly conserved
between Drosophila and man, but only about a third of the subunits
are conserved between yeast and man. Three other genes (brahma,
moira, and osa) encode subunits of a chromatin-remodeling
complex conserved from yeast to man. We have used genetic screens to identify
a number of other genes that interact with the brahma complex in regulating
two different homeotic genes targets. The brahma-interacting genes
tonalli and taranis encode zinc-finger and antifreeze proteins,
respectively. The trithorax group gene kismet encodes a
brahma-related protein that is a subunit of a third protein complex.
The kismet protein is also conserved between Drosophila and man
and appears to be a subunit of a chromatin-remodeling complex that is
not found in yeast. The verthandi gene, which is also required
for the transcriptional regulation of homeotic genes, has been mapped
to a heterochromatic chromosomal region that is not on the current molecular
maps of the Drosophila genome.
Transcriptional Repressors of Homeotic Genes
Kennison in collaboration with J. Müller, Tübingen, Germany
and A. Birve, Umea, Sweden
The initial domains of homeotic gene repression are set the by the segmentation
proteins, which also divide the embryo into segments. Maintenance of repression
requires the proteins encoded by the Polycomb group genes. The
switch from the initiation to the maintenance of repression involves the
recruitment of a chromatin-remodeling complex that includes the brahma-
and kismet-related protein Mi-2 and a histone deacetylase
subunit. Maintenance also requires the Polycomb complex, which
likewise has a histone deacetylase subunit. We have identified and characterized
a new Polycomb group gene, Su(z)12,that encodes a zinc-finger
protein and is required both maternally and zygotically for the maintenance
of homeotic gene repression. In collaboration with the Section on Gene
Expression, we have also begun a large genetic screen for new Polycomb
group genes.
Cis-Acting Sequences Required for Homeotic Gene Repression
Kennison, Cooper
Assays in transgenes in Drosophila have previously identified
cis-acting repressor elements from the homeotic genes. These cis-acting
repressor elements are called PREs (Polycomb group response elements).
We have used a large number of existing chromosomal rearrangements in
the Sex combs reduced homeotic gene to investigate the cis-acting
elements required for transcriptional repression. These chromosomal rearrangements
identify two genetic elements about 70 kb apart in the Sex combs reduced
gene that must be in cis to maintain proper repression. When not
physically linked to each other, the genetic elements interact with elements
on the homologous chromosome and cause derepression of its wild-type Sex
combs reduced gene. We are currently characterizing a mutant chromosome
that appears to carry a novel insertion of one of these elements.
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PUBLICATIONS
- Birve
A, Sengupta AK, Beuchle D, Larsson J, Kennison JA, Rasmusson-Lestander
A, Müller J. Su(z)12, a novel Drosophila Polycomb group
gene that is conserved in vertebrates and plants. Development 2001;128:3371-3379.
- Kennison
JA, Southworth JW. Transvection in Drosophila . Adv Genet
2001;46, in press.
- Schulze
S, Sinclair DAR, Silva E, Fitzpatrick KA, Singh M, Lloyd VK, Morin KA,
Kim J, Holm DG, Kennison JA, Honda BM. Essential genes in proximal
3L heterochromatin of Drosophila melanogaster. Mol Gen
Genet 2001;264:782-789.
- Southworth
JW, Kennison JA. Transvection and silencing of the Sex combs
reduced homeotic gene of Drosophila melanogaster.
Genetics 2002, in press.
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