Dynamics of epigenetic regulation
Mouse female trophoectoderm stem cells: The XIST non-coding RNA (green) shows partial overlap with the repressive H3K27Me3 histone mark on the inactive X chromosome (Morey et al.)
The Avner group combines genetics, genomics, biochemistry, and cell biology to study the nature of the key complex on the X chromosome responsible for X-inactivation.
Previous and current research
The genetic material of the cell is not all equally available for transcription and this availability, which varies with cell type and developmental stage, is mediated largely by epigenetic modifications to the genome playing out mainly at the level of the chromatin. The double focus of our research has been on mouse genetics and epigenetics, with a particular emphasis on the interface between genetics and epigenetics, as revealed using X-inactivation as an experimental paradigm. X-inactivation, which occurs early during development in female mammalian embryos, ensures the dosage compensation between females carrying two copies of the X chromosome and males with a single copy of the X. Parts of the process in the mouse can be modelled ex vivo using female ES cells. We have been at the forefront of research into the characterisation and functional analysis of the different components of the X-inactivation centre, the key complex on the X chromosome for the initiation of X-inactivation. Ongoing research involves, for instance, the study of the Xce locus (X-controlling element), a genetic locus existing in different forms, which appears to influence which of the two X chromosomes will be chosen to undergo X-inactivation, and studies on the basis of the differences in the stability of the X-inactivation process occurring in the different extra-embryonic lineages of the mouse.
By carrying out this research we are not only discovering the multiplicity and plasticity of mechanisms that feed into this process of epigenetic control but also providing insights into the links between epigenetic processes and development. Our approach involves a combination of genetics, genomics, biochemistry and cell biology and both ex vivo and in vivo experimental approaches.
Future projects and goals
Objectives of our future work will be to gain further mechanistic insights into variations in the X-inactivation process that occur in different cell lineages and the sensitivity of the process to trans-acting genetic factors. We will use our knowledge of the X-chromosome to explore more widely the contribution of epigenetic regulation to allele-specific epistasis, the process where the effects of one gene are modified in an allele-specific manner by one or several other genes.