Dynamics of facultative heterochromatin

Abstract

In these two lectures (2 and 3), I present the epigenetic regulation of the X chromosome. I begin the lecture by presenting the molecular basis of dose compensation strategies in different XX/XY species, such as the vinegar fly, Drosophila melanogaster and the nematode Caenorabditis elegans, in order to compare these very different dose compensation strategies with X inactivation in mammals. Sex determination and dose compensation are triggered by the same pathway in Drosophila and C. elegans - but not in mammals, where dose XX triggers X inactivation, whereas the presence of the Sry gene triggers male sex.

In 1961, Mary Lyon proposed, on the basis of genetic studies in mice, that in female mammals, one of the two X chromosomes becomes inactive, forming Barr's corpuscle. More precisely, she hypothesized that at the start of embryonic development, either the paternal or maternal X chromosome is inactivated in each cell, and that this inactive state is then propagated through cell divisions leading to cell mosaicism in females for the expression of X-linked genes.

Lyon's 1961 paper marked the beginning of the field of X-inactivation and a renaissance in epigenetics. This process, at the intersection of developmental biology and genetics, rapidly became a paradigm for epigenetics and heterochromatin formation. Thanks to studies on the inactive X chromosome, we could understand how chromatin organization influences genome function and gene expression in a developmental context.

In this lecture, I present the state of our current knowledge of this epigenetic process at the scale of a whole chromosome. In particular, I highlight the fact that some genes can escape inactivation, suggesting that some genes are more dose-sensitive than others - and this can vary from one individual to another and in different tissues. Differences in dose, and these variations in gene expression on X, could have important implications for differences between men and women - and between women. The following lectures focus on these considerations.