Many species have evolved a sex chromosome based sex determination system that often leads to a difference in sex chromosome copy number. Failure to compensate for this difference leads to expression disequilibrium that proves lethal for the organism. Dosage Compensation (DC) collectively refers to the strategies that correct for gene dosage imbalance between sexes and serves as an interesting problem to explore the interaction between chromosome organization and chromosome wide gene regulation. In C. elegans, DC is achieved by two-fold downregulation of X-linked genes in hermaphrodites (XX) upon recruitment of the Dosage Compensation Complex (DCC). GRO-seq studies have shown that loading of the DCC restricts RNA Polymerase II access via an unknown mechanism. DCC is a multiprotein complex structurally similar to mitotic condensins. Higher order chromatin structures have therefore long been suggested to influence X-linked transcription, but never tested. Here, we asked whether the DCC influences the spatial and structural organization of the X chromosome. Using microscopic measurements we find that loading of the DCC slightly increases compaction of the X chromosome in hermaphrodites compared to males. Moreover, our data shows that the entire X chromosome lies preferentially in close proximity to the nuclear periphery in males while it is internal positioned in hermaphrodites. Loss and gain of function experiments demonstrate that DCC loading in hermaphrodites impairs perinuclear localization. Moreover, a single motif enriched on X and sufficient for DCC loading in hermaphrodites (rex site), is able to autonomously target an autosomal locus to the nuclear periphery in males specifically. To identify X interactors at the periphery, we performed DNA Adenine Methyltransferase Analysis (DamID). This showed a male-specific interaction of the X chromosome with the nuclear pore subunit and not the lamina. Together, our results put forward a structural model of DC, in which X-specific sequences mediate interactions with nuclear pore proteins in males, thereby locating the X chromosome in transcriptionally active perinuclear domains, while DCC binding prevents this pore association in hermaphrodite; reversing the role of DCC from active repression to inhibition of activation. Currently, we focus on the characterization of factors involved in X chromosome activation in males, by screening for male-specific lethal factors using a candidate reverse genetic screen. .
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