Molecular antagonism between X-chromosome and autosome signals determines nematode sex

Abstract

Sex is determined in Caenorhabditis elegans by the ratio of X chromosomes to the sets of autosomes, the X:A signal. A set of genes called X signal elements (XSEs) communicates X-chromosome dose by repressing the masculinizing sex determination switch gene xol-1 (XO lethal) in a dose-dependent manner. xol-1 is active in 1X:2A embryos (males) but repressed in 2X:2A embryos (hermaphrodites). Here we showed that the autosome dose is communicated by a set of autosomal signal elements (ASEs) that act in a cumulative, dose-dependent manner to counter XSEs by stimulating xol-1 transcription. We identified new ASEs and explored the biochemical basis by which ASEs antagonize XSEs to determine sex. Multiple antagonistic molecular interactions carried out on a single promoter explain how different X:A values elicit different sexual fates. XSEs (nuclear receptors and homeodomain proteins) and ASEs (T-box and zinc finger proteins) bind directly to several sites on xol-1 to counteract each other's activities and thereby regulate xol-1 transcription. Disrupting ASE-and XSE-binding sites in vivo recapitulated the misregulation of xol-1 transcription caused by disrupting cognate signal element genes. XSE-and ASE-binding sites are distinct and nonoverlapping, suggesting that direct competition for xol-1 binding is not how XSEs counter ASEs. Instead, XSEs likely antagonize ASEs by recruiting cofactors with reciprocal activities that induce opposite transcriptional states. Most ASE-and XSE-binding sites overlap xol-1's -1 nucleosome, which carries activating chromatin marks only when xol-1 is turned on. Coactivators and corepressors tethered by proteins similar to ASEs and XSEs are known to deposit and remove such marks. The concept of a sex signal comprising competing XSEs and ASEs arose as a theory for fruit flies a century ago. Ironically, while the recent work of others showed that the fly sex signal does not fit this simple paradigm, our work shows that the worm signal does.

Sex-Specific Gene Expression and Life Span Regulation

“…The X/A ratio is counted by a mechanism involving multiple X chromosome-specific and autosome-specific sequence elements [9] . The X/A ratio regulates the on/off state of a binary switch gene Xol-1 , so that Xol-1 is off in females and on in males (Figure 1).…”

Nuclear receptors in nematode development: Natural experiments made by a phylum

“…This subsequently affects sex determination through the mechanism of X-chromosome dosage compensation [131]. SEX-1 inhibits xol-1 expression in cooperation with ONECUT homeodomain protein CEH-39 which is necessary together with SEX-1 for complete repression of xol-1 [132][133][134]. SEX-1 dependent repression of xol-1 is complemented by a second regulatory step at the RNA level through an RNA binding protein FOX-1 which has an additive effect in lethality caused by SEX-1 inactivation in XX-hermaphrodite animals [132][133][134].…”

The development of sexual dimorphism: studies of the Caenorhabditis elegans male

“…In C. elegans , sex is determined by the ratio of autosomes to sex chromosomes: one‐to‐one dictates hermaphrodite choice (naturally AA, XX), two‐to‐one dictates male choice (naturally AA, XO) . How this ratio inaugurates pathways leading to specification of sexual phenotype has been studied for many years by a number of laboratories and elucidated in considerable molecular detail …”