A key role for chromosome compartment interactions in Xist RNA localisation
Mammalian X-chromosome inactivation is regulated by the long non-coding RNA Xist. The basis of Xist localisation to specific sites along the inactivated chromosome is, however, still poorly understood. To investigate in situ Xist localisation, we established an MCPH1-deficient cell model that retains compacted interphase chromosomes, enabling visualisation of individualised chromosome territories. We find that preferred association sites for Xist RNA are arranged around the periphery of compacted chromosome territories both in undifferentiated and differentiated cells, and moreover that these sites correlate closely with A1-sub-compartments on the X chromosome. This peripheral positioning of A1-sub-compartments is prevalent across all chromosomes and is also a hallmark of early prophase. We further exploit MCPH1-deficiency to investigate models with excess levels of Xist RNA and following depletion of HNRNPU, a factor implicated in anchoring Xist RNA to chromosome territories. Together, our findings implicate compartment interactions as key determinants for Xist RNA localisation and spreading in cis along the chromosome.