A key role for chromosome compartment interactions in directing Xist RNA localisation

X-chromosome inactivation, the mechanism for dosage compensation in mammals, is orchestrated by the long non-coding RNA Xist which localises across the X chromosome in cis. The basis for in cis localisation remains poorly understood. To investigate in situ Xist localisation, we established MCPH1-deficient cell models that retain compacted interphase chromosomes, enabling visualisation of individualised chromosome territories. We find that Xist RNA is directed to sites around the periphery of compacted chromosome territories, and moreover that these sites correlate closely with A1-sub-compartments on the X chromosome. We further show that peripheral positioning of A1-sub-compartments occurs on all chromosomes and is a hallmark of early prophase. A key role for compartment interactions in Xist localisation is further supported by analysis of MCPH1-deficient models where Xist is overexpressed (from the X chromosome or an autosomal Xist transgene), and following depletion of HNRNPU, a key factor that anchors Xist RNA to chromosome territories.