One long-term goal is to understand the genetic switch that specifies sexual fate in the nematode C. elegans. Sex is determined in this and other organisms by an X-chromosome counting mechanism that distinguishes one X chromosome from two. X-chromosome dose by itself is not sufficient to determine sex. Instead, X-chromosome number is assessed relative to the sets of autosomes, the X:A ratio. We showed that a set of genes on X, called X-signal elements (XSEs), relays X-chromosome dose by repressing the activity of the sex determination switch gene xol-1 through both transcriptional and post-transcriptional mechanisms. Another set of genes called Autosomal-signal elements (ASEs) opposes the repressive activity of XSEs, allowing xol-1 activity to be high in XO embryos and low in XX embryos. Future work addresses how only a two-fold range in the concentration of regulators can specify two alternative sexual fates. One XSE is a nuclear hormone receptor (NHR) called SEX-1, a homolog of the retinoic acid receptor (RAR) gene family that participates in signaling pathways used for patterning and cellular differentiation in all metazoans. Disruptions in RARs are associated with human cancers, knowledge that has lead to the use of retinoids in the treatment of leukemias. Information gained from model organisms such as C. elegans about the genetic pathways in which NHRs function will provide an opportunity to discover other gene targets for drug therapy, which might be applicable to humans. A second long-term goal is understand the mechanism of Xchromosome dosage compensation, which equalizes X expression between the sexes. We defined a protein complex that binds both X chromosomes of XX animals to repress X expression by half. Members of the complex also play essential roles in the compaction and resolution of mitotic and meiotic chromosomes. We found that discrete, cis-acting sites on X act as entry sites to recruit the complex and to nucleate spreading of the complex along X. Future work addresses the molecular identity of the X-recognition sites, the mechanism of spreading, and the biochemical basis for repression. The link between chromosome segregation and gene expression has further implications for human disease.
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