Dual roles for nuclear RNAi Argonautes in Caenorhabditis elegans dosage compensation

Abstract

Dosage compensation involves chromosome-wide gene regulatory mechanisms which impact higher order chromatin structure and are crucial for organismal health. Using a genetic approach, we identified Argonaute genes which promote dosage compensation in C. elegans. Dosage compensation in C. elegans hermaphrodites is initiated by the silencing of xol-1 and subsequent activation of the Dosage Compensation Complex (DCC) which binds to both hermaphrodite X chromosomes and reduces transcriptional output by two-fold. A hallmark phenotype of dosage compensation mutants is decondensation of the X chromosomes. We characterized this phenotype in Argonaute mutants using X chromosome paint probes and fluorescence microscopy. We found that while nuclear Argonaute mutants hrde-1 and nrde-3, as well as mutants for the piRNA Argonaute prg-1, exhibit derepression of xol-1 transcripts, they also affect X chromosome condensation in a xol-1-independent manner. We also characterized the physiological contribution of Argonaute genes to dosage compensation using genetic assays and found that hrde-1 and nrde-3 contribute to healthy dosage compensation both upstream and downstream of xol-1.

How Chromatin Motor Complexes Influence the Nuclear Architecture: A Review of Chromatin Organization, Cohesins, and Condensins with a Focus on C. elegans

“…Tethering of heterochromatin is not unique to dosage compensation in C. elegans [121,122,180], but in conjunction with the DCC, it has a unique impact on the compaction and subnuclear localization of the X chromosomes. It has also been demonstrated that the nuclear RNAi machinery is also involved in X chromosome compaction and repression, but whether this effect is direct or indirect is not yet known [181]. A similar pathway involving Argonautes to establish heterochromatin has been observed in D. melanogaster [182].…”

XOL-1 regulates developmental timing by modulating the H3K9 landscape inC. elegansearly embryos

“…The DCC binds to recruitment sites on the X chromosome and spreads along the length of the chromosome to repress transcription [20], [21], [22], [23]. The DCC and the additional ancillary pathways it recruits use multiple mechanisms to establish and maintain dosage compensation on the hermaphrodite X chromosomes throughout somatic tissues in larvae and adults [24], [25], [26], [27], [28]. These include X-specific deposition of H4K20me1 repressive mark by DPY-21 [27], [28], [29], [30], tethering of H3K9me2/me3 regions to the nuclear lamina [25], contributions by the nuclear RNAi machinery [24], and the formation of TADs on the X chromosomes [26], [31].…”

“…The DCC and the addi,onal ancillary pathways it recruits use mul,ple mechanisms to establish and maintain dosage compensa,on on the hermaphrodite X chromosomes throughout soma,c ,ssues in larvae and adults [24], [25], [26], [27], [28]. These include X-specific deposi,on of H4K20me1 repressive mark by DPY-21 [27], [28], [29], [30], tethering of H3K9me2/me3 regions to the nuclear lamina [25], contribu,ons by the nuclear RNAi machinery [24], and the forma,on of TADs on the X chromosomes [26], [31]. The ini,a,on of dosage compensa,on in developing hermaphrodite embryos is linked to a loss in developmental plas,city and the onset of cellular differen,a,on programs [32], [33].…”