Restricting Dosage Compensation Complex Binding to the X Chromosomes by H2A.Z/HTZ-1

Abstract

Dosage compensation ensures similar levels of X-linked gene products in males (XY or XO) and females (XX), despite their different numbers of X chromosomes. In mammals, flies, and worms, dosage compensation is mediated by a specialized machinery that localizes to one or both of the X chromosomes in one sex resulting in a change in gene expression from the affected X chromosome(s). In mammals and flies, dosage compensation is associated with specific histone posttranslational modifications and replacement with variant histones. Until now, no specific histone modifications or histone variants have been implicated in Caenorhabditis elegans dosage compensation. Taking a candidate approach, we have looked at specific histone modifications and variants on the C. elegans dosage compensated X chromosomes. Using RNAi-based assays, we show that reducing levels of the histone H2A variant, H2A.Z (HTZ-1 in C. elegans), leads to partial disruption of dosage compensation. By immunofluorescence, we have observed that HTZ-1 is under-represented on the dosage compensated X chromosomes, but not on the non-dosage compensated male X chromosome. We find that reduction of HTZ-1 levels by RNA interference (RNAi) and mutation results in only a very modest change in dosage compensation complex protein levels. However, in these animals, the X chromosome–specific localization of the complex is partially disrupted, with some nuclei displaying DCC localization beyond the X chromosome territory. We propose a model in which HTZ-1, directly or indirectly, serves to restrict the dosage compensation complex to the X chromosome by acting as or regulating the activity of an autosomal repellant.

Condensins: universal organizers of chromosomes with diverse functions

“…Intriguingly, a recent study suggests that the DCC may not repress genes by direct binding; rather, the DCC may act at a distance, possibly by bringing dosage-compensated genes to the vicinity of DCC-bound sites (Jans et al 2009). Another study provided evidence that the histone H2A variant H2A.Z might function in dosage compensation through a mechanism that helps restrict the DCC to the X chromosome (Petty et al 2009). Thus, information from these studies on condensin I DC should provide a paradigm that will readily be applicable to our understanding of the general mechanisms of action of condensins.…”

Caenorhabditis elegans Dosage Compensation Regulates Histone H4 Chromatin State on X Chromosomes

“…Previous studies reported a decrease in HTZ-1 (histone H2A variant) occupancy (60,77) and decreased levels of H3K4me3 on dosage-compensated X chromosomes (59). Other work has shown an increase in nucleosome occupancy at X-linked gene promoters that is sequence, and not DCC, dependent (16).…”

HTZ-1/H2A.z and MYS-1/MYST HAT act redundantly to maintain cell fates in somatic gonadal cells through repression of ceh-22 in C. elegans

“…bet-1(os46) is a nonsense mutation (Shibata et al, 2010). bet-1(gk425), htz-1(tm2469) and mys-1(n4075) are deletions (Ceol and Horvitz, 2004;Whittle et al, 2008;Petty et al, 2009;Shibata et al, 2010). gk425 is a weak allele, because its phenotype is weaker than that of the null allele, os46 (Shibata et al, 2010).…”

“…HTZ-1 facilitates the transcriptional activation of the PHA-4 targets during foregut development (Updike and Mango, 2006). In addition, HTZ-1 restricts the dosage compensation complex that downregulates gene expression by ~50% along the X chromosome, suggesting positive transcriptional roles for HTZ-1 (Petty et al, 2009). A negative role for HTZ-1 in transcriptional regulation has not yet been reported.…”