The relationship between chromosome structure, nuclear positioning, and long-range gene regulation is poorly understood. To explore this relationship, we dissected X-chromosome-wide gene regulation enacted by a dosage compensation complex (DCC), which represses X transcription in hermaphrodites to balance gene expression between sexes. We inserted transgenes throughout the genome and queried their expression to determine whether different transcriptional environments exist on X and autosomes. Transgenes integrated on X were dosage compensated regardless of position, meaning their expression was equal in wild-type males and hermaphrodites but elevated in dosage-compensation-defective hermaphrodites. This result indicates the X chromosome is broadly permissive for repression, and endogenous genes that escape have special features enabling them to overcome this repression. In contrast, we found no chromosome-wide mechanism to balance X expression with that of autosomes, given that transgenes on X were expressed at half the level of transgenes on autosomes. Repression of X transgenes was independent of their proximity to DCC recruitment sites (rex), highlighting the long-range mechanism of regulation employed by the DCC. We already showed that changes in higher order X-chromosome structure accompany repression of X-linked genes, so we next explored whether spatial positioning of X influences dosage compensation. We first addressed a model of others that rex sites target X to the nuclear periphery in males to increase gene expression, and DCC binding to rex sites in hermaphrodites helps relocate X to the interior, thereby repressing X. Using FISH, we found for both sexes that neither endogenous rex sites on X nor ectopically inserted rex sites on autosomes were preferentially located at the nuclear periphery. Furthermore, though rex insertions on autosomes recruit the DCC, the expression of adjacent genes was not elevated in DCC-depleted animals. These observations disfavor the proposed model. Instead, we found that pairs of distant rex sites interact in a DCC-dependent manner, and interacting rex sites are preferentially located at the nuclear periphery compared to non-interacting sites. Interacting rex pairs associate with nuclear pores, not the lamina. We propose the nuclear pore might act as a scaffold to promote rex site interactions, which in turn influence gene expression by remodeling higher order chromosome structure.
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