Chromatin Remodeling in Dosage Compensation

Abstract

In many multicellular organisms, males have one X chromosome and females have two. Dosage compensation refers to a regulatory mechanism that insures the equalization of X-linked gene products in males and females. The mechanism has been studied at the molecular level in model organisms belonging to three distantly related taxa; in these organisms, equalization is achieved by shutting down one of the two X chromosomes in the somatic cells of females, by decreasing the level of transcription of the two doses of X-linked genes in females relative to males, or by increasing the level of transcription of the single dose of X-linked genes in males. The study of dosage compensation in these different forms has revealed the existence of an amazing number of interacting chromatin remodeling mechanisms that affect the function of entire chromosomes.

A male‐specific effect of dominant‐negative Fos

“…The phenotypes produced by the transgene in males synergize strongly with Notch pathway mutations. These data suggest that an aberrant form of Fos protein is capable of eliciting both loss of function and gain of function (neomorphic) phenotypes, the latter interfering with the mechanism of dosage compensation (Lucchesi et al, 2005).…”

“…The differential sensitivity of males suggested a possible involvement with dosage compensation mechanisms. Normally, male X chromosomes in Drosophila exhibit elevated transcription relative to each X chromosome of females by means of dosage compensation (reviewed in Lucchesi et al, 2005). If Fos bZip expression were to impact dosage compensation in addition to other developmental processes, then males could suffer from depressed expression of X chromosomal loci and therefore exhibit more prominent phenotypic effects than females.…”

“…The male-specific lethal loci: msl1-3, male lethal (mle) and males-absent on the first (mof), along with rox1 and roX2, encode components of the macromolecular complex that mediates dosage compensation (Lucchesi et al, 2005). The assembly of the complex requires a scaffold derived from the interaction of Msl1 and Msl2.…”

“…Msl1 also binds to the histone acetytransferase Mof protein (Hilfiker et al, 1997), which acetylates histone H4 at lysine 16 on nucleosomes (Smith et al, 2000). Further assembly of the complex involves the association of Msl3 with Msl1, and the association of Mle, an ATP-dependent helicase, with both Msl2 and roX RNAs (Lucchesi et al, 2005;Li et al, 2005Li et al, , 2008. This complex assembles only in males because msl2 RNA is not translated in females (Kelley et al, 1997).…”

“…Importantly, a leucine zipper like-motif within Msl1 protein was demonstrated to mediate association with Msl2 (Li et al, 2005). This association appears to form the scaffold for binding other components of the dosage compensation complex, as well as for DNA binding (Lucchesi et al, 2005;Li et al, 2005Li et al, , 2008. Therefore, one hypothesis to explain the male phenotypes from Fos bZip expression involves interference with the assembly of the complex through effects on Msl1 or Msl2.…”