title: 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.
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA.
authors.forename: Behnom
authors.initials: B
authors.lastname: Farboud
authors.forename: Paola
authors.initials: P
authors.lastname: Nix
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Jow
authors.forename: John M
authors.initials: JM
authors.lastname: Gladden
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Meyer
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001216:Asparagine; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000196:embryology / Q000235:genetics* / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002875:Chromosomes / Q000235:genetics*; D004251:DNA Transposable Elements / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004303:Dosage Compensation, Genetic; D004625:Embryo, Nonmammalian / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D017238:Genes, Helminth / Q000235:genetics; D005973:Glutamine; D018398:Homeodomain Proteins / Q000235:genetics; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D019849:Sex Determination Processes / Q000235:genetics*; D014158:Transcription, Genetic; D019895:Transposases / Q000235:genetics / Q000378:metabolism; D014960:X Chromosome / Q000235:genetics*
chemical_list: C582300:CEH-39 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D004251:DNA Transposable Elements; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D016601:RNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; C582299:SEA-2 protein, C elegans; C111652:mariner transposases; C115677:sex-1 protein, C elegans; D005973:Glutamine; C091429:XOL-1 protein, C elegans; D001216:Asparagine; D019895:Transposases
keywords: T-box protein; dosage compensation; dose-sensitive signals; haploinsufficiency; nuclear hormone receptor; sex determination