# SWI/SNF complexes modulate gene expression and the development of physical dependence to ethanol

## TL;DR

This study shows that in C. elegans, long-term ethanol exposure causes physical dependence and withdrawal behaviors linked to gene expression changes, with the SWI/SNF complex and lipid-related genes playing key roles.

## Contribution

The study identifies SWI/SNF chromatin remodeling and lipid metabolism genes as novel contributors to ethanol-induced physical dependence in C. elegans.

## Key findings

- 1870 genes show differential expression immediately after ethanol exposure but not after 6 hours of withdrawal.
- The SWI/SNF complex, particularly swsn-9, is required for normal withdrawal-induced bordering behavior.
- Genes involved in fatty acid metabolism and temperature sensitivity, like dod-24, are linked to ethanol dependence and withdrawal.

## Abstract

Long exposure to ethanol causes the development of physical dependence, which causes withdrawal symptoms when ethanol is removed. We exploited the rapid development of physical dependence in Caenorhabditis elegans (C. elegans) to examine the ethanol‐induced transcriptional changes that correspond with physical dependence and withdrawal effects.

After an 18‐h exposure to an intoxicating concentration of ethanol, we observe the development of physical dependence; withdrawal from ethanol causes an increase in their preference for thicker parts of a bacterial lawn, a behavior we term withdrawal‐induced bordering (WIB). We performed transcriptional analysis to identify genes whose expression changes correlate with WIB.

We found that WIB is transient, resolving within 6 h of removal from ethanol, suggesting it is driven by short‐term gene expression changes. We identified 1870 genes with differential expression immediately after ethanol exposure but not after 6 h of withdrawal; these are candidate mediators of WIB. We found that the SWI/SNF chromatin remodeling complex, known to be important in the response to acute ethanol exposure, is required for normal WIB. Loss of swsn‐9 attenuated but did not eliminate WIB, suggesting that there are swsn‐9‐dependent and swsn‐9‐independent components of WIB. Regulation of 1031 ethanol‐responsive genes requires swsn‐9. WIB phenocopies reduced npr‐1 activity, and two genes implicated in the npr‐1 signaling pathway, jmjc‐1 and dod‐24, were transiently regulated after extended ethanol exposure. dod‐24 mutants have attenuated WIB.

Extended exposure to ethanol causes the development of transient physical dependence in C. elegans, and the SWI/SNF complex is involved in this process. Genes involved in fatty acid metabolism were regulated over the WIB timecourse, and dod‐24, which is involved in temperature sensitivity, is required for normal WIB. Together, these results suggest a model in which modulation of lipid membrane composition may be one mechanism for the development of physical dependence on ethanol.

The development of physical dependence on ethanol is an important component of alcohol addiction because dependent individuals experience withdrawal symptoms during acute abstinence. This study used C. elegans to identify gene expression changes accompanying physical dependence. SWI/SNF chromatin remodeling contributed significantly to dependence. Regulation of lipid genes, including some involved in temperature responses, was correlated with withdrawal. This suggests that these responses may share molecular mechanisms and may point to a role for modifying membrane structure in developing physical dependence.