An MLL/COMPASS subunit functions in the C. elegans dosage compensation complex to target X chromosomes for transcriptional regulation of gene expression

Abstract

Here we analyze the essential process of X-chromosome dosage compensation (DC) to elucidate mechanisms that control the assembly, genome-wide binding, and function of gene regulatory complexes that act over large chromosomal territories. We demonstrate that a subunit of Caenorhabditis elegans MLL/COMPASS, a gene activation complex, acts within the DC complex (DCC), a condensin complex, to target the DCC to both X chromosomes of hermaphrodites for chromosome-wide reduction of gene expression. The DCC binds to two categories of sites on X: rex (recruitment element on X) sites that recruit the DCC in an autonomous, sequencedependent manner, and dox (dependent on X) sites that reside primarily in promoters of expressed genes and bind the DCC robustly only when attached to X. We find that DC mutations that abolish rex site binding greatly reduce dox site binding but do not eliminate it. Instead, binding is diminished to the low level observed at autosomal sites in wild-type animals. Changes in DCC binding to these non-rex sites occur throughout development and correlate directly with transcriptional activity of adjacent genes. Moreover, autosomal DCC binding is enhanced by rex site binding in cis in X-autosome fusion chromosomes. Thus, dox and autosomal sites have similar binding potential but are distinguished by linkage to rex sites. We propose a model for DCC binding in which low-level DCC binding at dox sites is dictated by intrinsic properties correlated with high transcriptional activity. Sex-specific DCC recruitment to rex sites then enhances the magnitude of DCC binding to dox sites in cis, which lack high affinity for the DCC on their own. We also show that the DCC balances X-chromosome gene expression between sexes by controlling transcription.

RNA Polymerase II transcription elongation and Pol II CTD Ser2 phosphorylation

“…CTD phosphorylation patterns in C. elegans are similar to other metazoans. Genome-wide studies show that Ser5-P shows stronger signal toward the promoter and Ser2 phosphorylation within the body of the genes 151,152 (for a review see ref. …”

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

“…xol-1 also controls the level of X-linked gene expression, and hence viability, by regulating the process of X-chromosome dosage compensation (Miller et al 1988;Chuang et al 1994;Rhind et al 1995;Dawes et al 1999). xol-1 coordinately regulates both sex determination and dosage compensation by negatively regulating the feminizing switch gene sdc-2 (sex determination and dosage compensation), which triggers assembly of all dosage compensation complex (DCC) subunits onto both X chromosomes of XX embryos to reduce X-linked gene expression by half (Dawes et al 1999;Pferdehirt et al 2011). sdc-2 also induces hermaphrodite sexual differentiation by repressing the autosomal male sex-determining gene her-1.…”

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

“…The XO hermaphrodite strain TY2205 bears three mutations: her-1(e1520) and xol-1(y9) mutations result in hermaphrodite sexual fate; sdc-3(y126) mutation disables dosage compensation. TY2205 larvae are viable phenotypic hermaphrodites that do not activate dosage compensation (Csankovszki et al 2009;Pferdehirt et al 2011). The XX male strain CB5362 contains tra-2(ar221) that results in male sexual fate and xol-1 (y9) that enhances masculinization (Hodgkin 2002).…”