Karl Friedrich Bonhoeffer Award Lecture: Exploring the dynamic relationship between gene expression and chromosome organisation during X-chromosome inactivation

X-chromosome inactivation during early female development is an essential epigenetic process that is required to achieve appropriate dosage for X-linked gene products. We are interested in understanding how the differential treatment of the two X chromosomes in the same nucleus is set up during development and how this differential expression is then maintained, or reversed in certain circumstances, either normally or in a disease context such as cancer. The establishment of X inactivation involves the non-coding Xist RNA that triggers chromosome-wide chromatin re- organisation and gene silencing. Recent insights have been made into the nature of these chromosome-wide changes, including the global loss of topologically associated domains (TADs)1,2,3. However little is known about the underlying mechanisms and the precise relationship between 3D chromosome structure and altered gene expression states on the X chromosome. Results of our recent studies, using a combination of single-cell chromosome-conformation capture technologies and high-resolution microscopy in differentiating embryonic stem cells and in vivo mouse embryos, will be presented and the implications for development and disease will be dicussed.

1. Nora, E.P. et al (2012). Spatial partitioning of the regulatory landscape of the X- inactivation centre. Nature 485, 381–385.
2. Giorgetti, L. et al (2014) Predictive polymer modeling reveals coupled fluctuations in chromosome conformation and transcription. Cell, 157: 950–963
3. Giorgetti L., Lajoie, B., Carter, A.C., Attia, M. et al (2016) Structural organization of the inactive X chromosome. Nature 535: 575-579.