The Disteche lab research is focused on understanding the structure and functions of the sex chromosomes.
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 the testis-determining gene on the Y, a small chromosome that retains genes homologous to a subset of X-linked genes and genes involved in male-specific functions. Both males and females have two sets of autosomes in their somatic cells. Dosage compensation mechanisms have evolved to balance gene expression in both males and females. In females, a well-known mechanisn of dosage compensation called X inactivation silences one of the two X chromosomes to and equalize gene expression between the sexes (Lyon, 1961). A subset of genes escape X inactivation, i.e. they are expressed from both active and inactive X chromosomes, which causes sex differences due to higher expression in females (Berletch et al., 2011; Fang et al., 2021).
A second mechanism of dosage compensation achieves a balanced expression between the single active X chromosome and the autosomes in both sexes. This is done by increasing the output from genes on the active X chromosome in both sexes, a type of regulation that we demonstrated for the first time and called X upregulation (Nguyen and Disteche, 2006; Disteche, 2012).
Figure 1. The nucleus from a female cell (at left) cantains two X chromosomes (XX), one being upregulated (pink glow) to balance expression with autosomes (AA) present in two copies, while the other X chromosome is mostly silenced (black) by X inactivation, although some genes escape silencing (glow). The nucleus from a male cell (at right) contains an X chromosome, which is upregulated to balance expression with autosomes present in two copies (AA) and a Y chromosome.
We study the structure of the sex chromosomes in relation to development and cell functions using single-cell approaches and chromatin conformation analyses to characterize specific cell types and their developmental trajectories. Notably, we have shown that the inactive X chromosome forms a bipartite structure (Figure 2).
Figure 2. Hi-C generated contact maps of the active (left) and inactive X chromosome (right) shows the inactive X chromosome to be condensed in two superdomains separated by Dzx4 (Deng et al., 2015; Bonora et al., 2018).
Current Research
Our research group is especially interested in following changes in X chromosome expression and structure during embryonic development and in adulthood. We originally found that genes that escape X inactivation can be flanked by chromatin insulator elements (Filippova et al., 2005), and we are currently pursuing an analysis of the molecular determinants of escape at the level of the chromatin loop structure.
Our goal is to follow allelic changes in gene expression and configuration during mouse development. Escape genes play an important role in sex chromosome disorders in humans and have a strong impact on sex differences. To understand this, we derived unique human pluripotent stem cells to study sex differences and the role of sex chromosomes in healthy tissues and in disease.