Dosage compensation is the process that ensures equal levels of X-linked gene products in males and females in species in which the sexes differ in the number of X chromosomes they possess. In Drosophila, dosage compensation is achieved by doubling the transcript levels of X-linked genes in males. During the past 10 years there has been enormous progress in understanding both how dosage compensation is controlled in flies so that it happens only in males, as well as the manner in which it works to modulate the level of transcription of the X chromosome. Dosage compensation in flies is mediated by 6 protein coding genes [maleless (mle), male-specific lethal-1(msl-1), male-specific lethal-2 (msl-2), male-specific lethal-3 (msl-3), male (?) absent on the first (mof), and JIL-1 kinase], collectively referred to here as the msl genes, together with the non-coding RNA products of two additional genes, roX1 and roX2 (roX = RNA on the X).
There is substantial evidence that the products of all of these genes
function together in a complex, termed the compensasome, to mediate dosage
compensation by altering the chromatin structure of the X chromosome in
males. The products of these genes are all specifically associated
with the same set of hundreds of sites along the male X chromosome Figures
1, 2), and all of the MSL proteins and at least one of the ROX RNAs must
be present for the association of the compensasome with these sites. The
requirement that all the MSL proteins be present for the compensasome to
form allows dosage compensation to be made male-specific by preventing
the production of just one component in females. Indeed, translation
of msl-2 transcripts is repressed by the protein product of the female-specific,
master sex determination gene, Sex-lethal (Sxl). Therefore, in females,
MSL-2 protein is not generated, so active compensasomes do not form.
The likely mechanism by which the compensasome alters chromatin structure (thereby leading to hypertranscription) is via the modification of histones. An isoform of histone H4 acetylated at lysine 16, H4Ac16, is enriched at a set of sites on the male X chromosome whose locations correlate with the sites where compensasomes are found. The mof gene encodes a histone acetyltransferase, and a partially purified complex containing MOF is able to acetylate histone H4 specifically at lysine 16, as is recombinant MOF alone. That a second histone modification may be involved in dosage compensation has been suggested by the finding that JIL-1 kinase is associated with the compensasome, and phosphorylates histone H3 at ser10. Thus modifications of histones are a fundamental part of dosage compensation, as they are of transcriptional regulation more generally.
One focus of our current research on dosage compensation is on understanding
how the distribution of compensasomes along the X chromosome is achieved.
Almost everything known about the distribution of compensasomes along the
male X comes from examination of polytene salivary chromosomes. The
relevant facts are as follows. In wild type there are several hundred sites
at which compensasomes are found along the X chromosome. These sites
are reproducible both between cells and between organisms. Although the
places where compensasomes are found along the X chromosome are referred
to by all of us in the field as ‘sites’, they are in fact not points,
but rather bands
(small segments of chromosome) that roughly span the size range of salivary
chromosome bands seen with DNA stains (i.e. a few 10’s to several 100’s
of kb in length) (Figure 3). The compensasome bands do not correspond
to the bands where DNA is condensed. An understanding of the distribution
of compensasomes along the X chromosome needs to encompass not only how
compensasomes get to these several hundred sites, but also how the ends
of each compensasome band are delimited. To address these goals we
are using both molecular and cytogenetic approaches to dissect the processes
that govern the distribution of compensasomes along the male X chromosome
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