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
 
 
 
 
 
 
 
 
 

Original research publications.

Kernan, M. J., Kuroda, M. I., Kreber, R., Baker, B. S., and Ganetzky, B. (1991).  napts, a mutation affecting sodium channel activity in Drosophila, is an allele of mle, a regulator of X chromosome transcription.  Cell 66: 949-961.

Gorman, M., Kuroda, M. and Baker, B.S. (1993). Regulation of the sex-specific binding of the maleless dosage compensation protein to the male X chromosome in Drosophila.  Cell, 72: 39-49.

Gorman, M., Franke, A., and Baker, B. S., (1995) Molecular characterization of the male-specific lethal-3 gene and investigations of the regulation of dosage compensation in Drosophila. Development, 121:  463-475.

Bashaw, G. J., and Baker, B. S. (1995).  The msl-2 dosage compensation gene of Drosophila encodes a putative DNA-binding protein whose expression is sex-specifically regulated by Sex-lethal.  Development, 121:  3245-3258.

Franke, A., Dernberg, A., Bashaw, G. J., and Baker, B. S. (1996).  Evidence that MSL mediated dosage compensation in Drosophila begins at blastoderm.  Development 122: 2751-2760.

Marín, I., Franke, A., Bashaw, G. J., and Baker, B. S. (1996).  Dosage compensation in flies:  a regulatory system adapting to chromosome evolution.. Nature, 383:  160-163.

Bashaw, G. J., and Baker, B. S., (1997) The regulation of the Drosophila msl-2 gene reveals a function for Sex-lethal in translational control.  Cell, 89:  789-798.

Franke, A. and Baker, B. S., (1999)  The rox1 and rox2 RNAs are essential components of the Compensasome, which mediates dosage compensation in Drosophila.  Molec. Cell 4: 117-122.

Marin, I., and Baker, B. S. (2000).  Origin and evolution of the regulatory gene male-specific lethal 3. Mol. Biol. Evol.17: 1240-1250.
 

Reviews.

Baker, B. S., Marin, I., and Gorman, M. (1994) Dosage compensation in Drosophila.  Annu. Rev. Genetics, 28:  491-521.

Bashaw, G. J., and Baker, B. S. (1996).  Dosage Compensation and chromatin structure in Drosophila.  Curr. Opinions in Genet. and Dev. 496-501.

Franke, A. and Baker, B. S., (2000). Dosage compensation rox!  Curr. Opinion in Cell Biol. 12:351-354.

Marin, I., Siegal, M. L. and Baker, B. S.,  (2000).  The evolution of dosage compensation mechanisms.  BioEssays, 22:  1106-1114.