Work in the lab centres on understanding the molecular mechanism of X chromosome inactivation, the process mammals use to equalise levels of expression of genes on the X chromosome in females relative to males. X inactivation is initiated by expression of a non-coding RNA, Xist, that coats the chromosome from which it is transcribed, bringing about chromatin modifications that in turn lead to heritable gene silencing. We are interested in how X inactivation is regulated in early development, how X chromosome silencing is established and maintained, and how specific pluripotent lineages can reverse stable silencing of the inactive X.
To address these questions we are combining genetic, cell biological, biochemical and embryology approaches to analyse the role of epigenetic mechanisms such as DNA methylation, RNAi, histone tail modifications, variant histones and chromosome organisation. A central strategy for future work is to identify novel factors involved in epigenetic regulation using both RNAi based loss of function screens and biochemical screens carried out using as bait, factors defined in work to date. Through studying epigenetic mechanisms in X inactivation we aim to better understand their wider role in regulating the genome during differentiation and development.
hnRNPK Recruits PCGF3/5-PRC1 to the Xist RNA B-Repeat to Establish Polycomb-Mediated Chromosomal Silencing.
Pintacuda G. et al, (2017), Mol Cell, 68, 955 - 969.e10
Polycomb complexes in X chromosome inactivation.
Brockdorff N., (2017), Philos Trans R Soc Lond B Biol Sci, 372
Heard E. and Brockdorff N., (2017), 372
Heard E. and Brockdorff N., (2017), Philosophical Transactions of the Royal Society B: Biological Sciences, 372
Polycomb complexes in X chromosome inactivation
Brockdorff N., (2017), Philosophical Transactions of the Royal Society B: Biological Sciences