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bioRxiv · 10.64898/2026.04.17.719318

Loss of autism-associated gene wac alters social behavior and identifies cho-1 as a modulator of cholinergic signaling in C. elegans

Kim, D.-W.·Boonpraman, N.·Kuhn, N. C.·Sammi, S. R.
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Abstract

WAC is a chromatin-associated regulatory protein involved in transcriptional control and has been identified as an autism-associated gene in human genetic studies. However, its functional role in regulating behavior and synaptic processes remains incompletely understood. Using Caenorhabditis elegans, we investigated the consequences of wac deficiency on food-associated social behavior, growth-associated phenotypes, and cholinergic pathway function. wac-deficient worms showed a marked reduction in food-leaving behavior, supporting impaired behavioral responsiveness to food-associated environmental cues, while aggregation behavior was not significantly altered. PHX2587 wac deletion mutant worms also exhibited reduced body length, decreased pharyngeal pumping, and shortened lifespan, indicating broader growth and physiological impairment. Stage-resolved analysis of cholinergic pathway genes revealed stage-associated transcriptional changes, with coordinated upregulation of multiple presynaptic and postsynaptic cholinergic components (ace-1, cha-1, cho-1, lev-1, lev-10, unc-17, unc-29, unc-38, and unc-50) emerging most prominently at the young adult stage. Functional RNAi analysis further identified cho-1, which encodes the high-affinity presynaptic choline transporter, as a genotype-specific modifier of cholinergic sensitivity in PHX2587 worms. Importantly, cho-1 RNAi not only reduced aldicarb hypersensitivity but also partially suppressed the reduced body length phenotype and improved food-leaving behavior in PHX2587 worms, while having limited effects in wild-type N2. Together, these findings support a functional relationship between wac deficiency and cho-1-associated cholinergic modulation, suggesting that presynaptic choline transport contributes to selected behavioral and physiological consequences of wac loss. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/719318v2_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@cd8950org.highwire.dtl.DTLVardef@1f1e6adorg.highwire.dtl.DTLVardef@5f783dorg.highwire.dtl.DTLVardef@1cf0ed6_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

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Kim, D.-W., Boonpraman, N., Kuhn, N. C., Sammi, S. R.. 2026-04-21. Loss of autism-associated gene wac alters social behavior and identifies cho-1 as a modulator of cholinergic signaling in C. elegans. https://doi.org/10.64898/2026.04.17.719318

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