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Summary of Research

Figure 1

Male and female mammals differ by their sex chromosomes (Fig. 1). Males have one single X chromosome and a Y chromosome, while females have two X chromosomes. Sex is determined by a testis-determining gene on the Y, a small chromosome that contains mostly genes involved in male-specific functions. Both males and females have two sets of autosomes in their somatic cells. While dosage compensation is often thought of as a mechanism to equalize gene expression between the sexes, a far more important role is to achieve a balanced expression between the X and the autosomes. In mammals, this is done by doubling the output from genes on the active X chromosome in both sexes, a type of regulation that we recently discovered and called X up-regulation (Nguyen and Disteche, 2006). In females, a second form of dosage compensation, X inactivation, silences one of the two X chromosomes to avoid hyper-expression.

Figure 2

Our goal is to understand the mechanisms of dosage compensation by X up-regulation of the single active X chromosome of males and females in terms of molecular processes. We found that X-linked genes are highly expressed in brain, a finding relevant to the prevalence of X-linked mental retardation. A second aspect of our research concerns genes that escape X inactivation, i.e. genes expressed from the active and inactive X chromosomes (Fig. 2). We have discovered that genes that escape X inactivation are flanked by chromatin insulator elements (Fig. 3) (Filippova et al. 2005). We have also found that expression of a subset of genes that escape X inactivation is increased in specific tissues in females. Such genes play an important role in sex chromosome disorders. Our current projects are:

Figure 3

X up-regulation and increased expression in brain. We are determining the types of epigenetic modifications that regulate the active X chromosome in brain and other tissues and in stem cell lines before and after differentiation.

Regulation and impact of escape from X inactivation. We are currently investigating the chromatin structure of domains containing genes that escape X inactivation using chromosome-wide assays. The impact of escape genes in eliciting sex-specific differences and abnormal phenotypes in sex chromosome disorders is another area of interest.