Untangling the Contributions of Sex-Specific Gene Regulation and X-Chromosome Dosage to Sex-Biased Gene Expression in Caenorhabditis elegans

Abstract

Dosage compensation mechanisms equalize the level of X chromosome expression between sexes. Yet the X chromosome is often enriched for genes exhibiting sex-biased, i.e., imbalanced expression. The relationship between X chromosome dosage compensation and sex-biased gene expression remains largely unexplored. Most studies determine sex-biased gene expression without distinguishing between contributions from X chromosome copy number (dose) and the animal's sex. Here, we uncoupled X chromosome dose from sex-specific gene regulation in Caenorhabditis elegans to determine the effect of each on X expression. In early embryogenesis, when dosage compensation is not yet fully active, X chromosome dose drives the hermaphrodite-biased expression of many X-linked genes, including several genes that were shown to be responsible for hermaphrodite fate. A similar effect is seen in the C. elegans germline, where X chromosome dose contributes to higher hermaphrodite X expression, suggesting that lack of dosage compensation in the germline may have a role in supporting higher expression of X chromosomal genes with female-biased functions in the gonad. In the soma, dosage compensation effectively balances X expression between the sexes. As a result, somatic sex-biased expression is almost entirely due to sex-specific gene regulation. These results suggest that lack of dosage compensation in different tissues and developmental stages allow X chromosome copy number to contribute to sex-biased gene expression and function.KEYWORDS dosage compensation; C. elegans; RNA-seq; sex; sex-biased gene expression; chromatin; X chromosome; transcription; gene regulation; germline; XO; genetics of sex M ALES and females exhibit many phenotypic differences, termed sexual dimorphisms. With the exception of the gene-poor Y chromosome, the two sexes share identical genomes. Thus, sexual dimorphisms stem from differences in gene expression between sexes. Genes that are expressed differently between sexes include those expressed exclusively (sex specific) or at a higher level in one sex (sex biased). Sexbiased expression allows a gene to be more active in the sex that it benefits without a potential cost to the opposite sex. Sex-biased gene expression is common throughout metazoans. Previous studies indicate up to 60% of all genes show sex-biased expression [in mice (Khil et al. 2004;Yang et al. 2006;Reinius et al. 2012), flies (Parisi et al. 2003;Ranz et al. 2003;Allen et al. 2013;Kaiser and Bachtrog 2014), and nematodes (Reinke et al. 2004;Thomas et al. 2012;Albritton et al. 2014)].Previous genome-wide studies found that compared to autosomes, the X chromosome generally harbors more genes with female-biased expression and fewer genes with malebiased expression [in mice (Khil et al. 2004;Yang et al. 2006;Reinius et al. 2012), flies (Parisi et al. 2003;Ranz et al. 2003), and nematodes (Reinke et al. 2004;Thomas et al. 2012;Albritton et al. 2014)]. However, this observed enrichment of female bias and depletion of male bias from the X is a gene...

Caenorhabditis elegans Dosage Compensation: Insights into Condensin-Mediated Gene Regulation

“…The escapers might have appeared as such due to incomplete dosage compensation in early embryos [77]. Indeed, analysis of several sex determination mutants failed to identify large groups of escapers in larval worms [77, 79]. Additionally, a reporter transgene integrated into several ectopic X sites was consistently repressed by the DCC, supporting a chromosome-wide mechanism of repression [80].…”

“…DCC represses transcription by reducing RNA Pol II binding to X-chromosome promoters [33, 77, 78][77, 79, 80].…”

When and how do sex‐linked regions become sex chromosomes?

“…At all stages of degeneration of a nonrecombining region, the rates also depend on the specific properties of the genes present (e.g., Kramer et al 2016;Rifkin et al 2020;Bellott and Page 2021). A striking example is the neo-Y of D. busckii, which is more degenerated (with 58% nonfunctional genes) than the larger and older one in D. miranda (only 34% nonfunctional genes), probably because the latter evolved from a "dot" chromosome, whose genes show low selective constraints (Zhou and Bachtrog 2015).…”

Binding of an X-specific condensin correlates with a reduction in active histone modifications at gene regulatory elements

“…Condensin DC interacts with additional subunits necessary for DCC binding and function ( Figure 1A). The DCC specifically binds to both hermaphrodite X chromosomes and represses each by half to equalize X chromosomal transcript levels between XX hermaphrodites and XO males [8][9][10].…”

“…Global run on (GRO-seq) [10] and chromatin immunoprecipitation sequencing (ChIP-seq) [8] analyses showed that the DCC is required to reduce RNA Pol II binding at X chromosomal promoters. DCC mediated repression appears to be chromosome-wide, with no large groups of genes escaping from dosage compensation [8,9]. Previous work has highlighted multiple roles for the DCC in regulation of X chromosome structure; DCC is required for the ~40% compaction of the X compared to autosomes [15], the regulation of subnuclear localization of the X chromosomes [16,17], and the regulation of topologically associating domains (TAD) on the X [18,19].…”