Unexpected Role for Dosage Compensation in the Control of Dauer Arrest, Insulin-Like Signaling, and FoxO Transcription Factor Activity inCaenorhabditis elegans

Abstract

During embryogenesis, an essential process known as dosage compensation is initiated to equalize gene expression from sex chromosomes. Although much is known about how dosage compensation is established, the consequences of modulating the stability of dosage compensation postembryonically are not known. Here we define a role for the Caenorhabditis elegans dosage compensation complex (DCC) in the regulation of DAF-2 insulin-like signaling. In a screen for dauer regulatory genes that control the activity of the FoxO transcription factor DAF-16, we isolated three mutant alleles of dpy-21, which encodes a conserved DCC component. Knockdown of multiple DCC components in hermaphrodite and male animals indicates that the dauer suppression phenotype of dpy-21 mutants is due to a defect in dosage compensation per se. In dpy-21 mutants, expression of several X-linked genes that promote dauer bypass is elevated, including four genes encoding components of the DAF-2 insulin-like pathway that antagonize DAF-16/FoxO activity. Accordingly, dpy-21 mutation reduced the expression of DAF-16/FoxO target genes by promoting the exclusion of DAF-16/FoxO from nuclei. Thus, dosage compensation enhances dauer arrest by repressing X-linked genes that promote reproductive development through the inhibition of DAF-16/FoxO nuclear translocation. This work is the first to establish a specific postembryonic function for dosage compensation in any organism. The influence of dosage compensation on dauer arrest, a larval developmental fate governed by the integration of multiple environmental inputs and signaling outputs, suggests that the dosage compensation machinery may respond to external cues by modulating signaling pathways through chromosome-wide regulation of gene expression.

A histone H4 lysine 20 methyltransferase couples environmental cues to sensory neuron control of developmental plasticity

“…5B). Therefore, ins-9 overexpression recapitulated the phenotype caused by set-4 and dpy-21 mutations (Dumas et al, 2013) (Fig. 1B).…”

Dynamic Control of X Chromosome Conformation and Repression by a Histone H4K20 Demethylase

“…DPY−21's DCC-independent activity is relevant for recent findings that DPY−21 modulates nematode growth and metabolism through the TORC2 pathway (Webster et al, 2013) and entry into the quiescent dauer state through the insulin-signaling pathway (Delaney et al, 2017; Dumas et al, 2013). Evidence in both cases suggests at least partial DCC-independence for DPY−21's functions.…”

A non-canonical role for the C. elegans dosage compensation complex in growth and metabolic regulation downstream of TOR complex 2

“…dpy-21 also modulates development through negative regulation of the insulin signaling pathway (Dumas et al, 2013). Unlike in TORC2 signaling, the findings of K. Dumas and P. Hu show that dpy-21 acts in its canonical role in dosage compensation as male dauer diapause entry was not affected.…”