Linking dosage compensation and X chromosome nuclear organization inC. elegans

Abstract

A nimal sex is determined by the number of X chromosomes in many species, creating unequal gene dosage (aneuploidy) between sexes. Dosage Compensation mechanisms equalize this dosage difference by regulating X-linked gene expression. In the nematode C. elegans the current model suggests that DC is achieved by a 2-fold transcriptional downregulation in hermaphrodites mediated by the Dosage Compensation Complex (DCC), which restricts access to RNA Polymerase II by an unknown mechanism. Taking a nuclear organization point of view, we showed that the male X chromosome resides in the pore proximal subnuclear compartment whereas the DCC bound to the X, inhibits this spatial organization in the hermaphrodites. Here we discuss our results and propose a model that reassigns the role of DCC from repression of genes to inhibition of activation.

Chromosome-wide mechanisms to decouple gene expression from gene dose during sex-chromosome evolution

“…First, the nuclear positioning model predicts that in males the transgenes on X should have elevated expression relative to transgenes on autosomes due to a rex -dependent association of X with the nuclear periphery. However, we found that in males, expression of single-copy transgenes on the sole X chromosome was not different from expression of single-copy transgenes inserted on only one of two homologous autosomes ( Figure 6C ), contrary to the nuclear positioning model of dosage compensation ( Sharma et al, 2014 ; Sharma and Meister, 2015 ).…”

“…Our analysis of X-chromosome regulation enabled us to evaluate an attractive but speculative model of X-chromosome dosage compensation, which posits that repression of X-linked gene expression in XX animals by the DCC is merely the result of escaping from a chromosome-wide mechanism that upregulates X expression ( Sharma et al, 2014 ; Sharma and Meister, 2015 ). In particular, these authors proposed that rex sites target X to the nuclear periphery in males to increase chromosome-wide gene expression, while DCC binding to rex sites in hermaphrodites blocks the peripheral localization, relocating X to the interior and hence reducing X gene expression.…”

“…Finally, our analysis of X-chromosome regulation, combined with chromosome localization studies, allowed us to evaluate a recent, speculative model of X-chromosome dosage compensation, which proposes that rex sites target X chromosomes to the nuclear periphery in males to increase gene expression, while DCC binding to rex sites in hermaphrodites relocates X to the interior, thereby reducing gene expression to achieve dosage compensation ( Sharma et al, 2014 ; Sharma and Meister, 2015 ). Results presented here provide strong evidence against this model of dosage compensation.…”

Dosage compensation of the sex chromosomes and autosomes

“…Factors involved in location of the active X, which is often located near the nuclear membrane in mammals, remain to be determined. In Drosophila and C. elegans , nuclear pore complexes associate with the active X chromosome, consistent with a specific nuclear location [125, 126]. …”

Dosage compensation and nuclear organization: cluster to control chromosome-wide gene expression

“…In males, the X chromosome interacts with nucleoporins, creating an activating compartment able to increase X-linked genes expression. In hermaphrodites, DCC loading onto X chromatin on the one hand increases overall chromosome compaction and TAD structure while on the other hand it impairs activation at pores by masking the interaction sites and altering X chromosome position [53,59]. How these changes ultimately impact RNA polymerase levels on the X remains to be elucidated.…”