The C. elegans miR-235 regulates the toxicity of graphene oxide via targeting the nuclear hormone receptor DAF-12 in the intestine

Abstract

The increased application of graphene oxide (GO), a new carbon-based engineered nanomaterial, has generated a potential toxicity in humans and the environment. Previous studies have identified some dysregulated microRNAs (miRNAs), such as up-regulated mir-235, in organisms exposed to GO. However, the detailed mechanisms of the dysregulation of miRNA underlying GO toxicity are still largely elusive. In this study, we employed Caenorhabditis elegans as an in vivo model to investigate the biological function and molecular basis of mir-235 in the regulation of GO toxicity. After low concentration GO exposure, mir-235 (n4504) mutant nematodes were sensitive to GO toxicity, implying that mir-235 mediates a protection mechanism against GO toxicity. Tissue-specific assays suggested that mir-235 expressed in intestine is required for suppressing the GO toxicity in C. elegans. daf-12, a gene encoding a member of the steroid hormone receptor superfamily, acts as a target gene of mir-235 in the nematode intestine in response to GO treatment, and RNAi knockdown of daf-12 suppressed the sensitivity of mir-235(n4503) to GO toxicity. Further genetic analysis showed that DAF-12 acted in the upstream of DAF-16 in insulin/IGF-1 signaling pathway and PMK-1 in p38 MAPK signaling pathway in parallel to regulate GO toxicity. Altogether, our results revealed that mir-235 may activate a protective mechanism against GO toxicity by suppressing the DAF-12-DAF-16 and DAF-12-PMK-1 signaling cascade in nematodes, which provides an important molecular basis for the in vivo toxicity of GO at the miRNA level.

Male gonad-enriched microRNAs function to control sperm production inC. elegans

“…In addition to mir-58.1, mir-83, mir-235, and mir-4807-4810.1, five miRNAs were identified to promote sperm production in conditions of moderate temperature stress (25ºC). This is consistent with the model that miRNAs function to buffer environmental stressors possibly by acting as fine tuners of gene expression (Burke et al 2015;Isik et al 2016;Tran et al 2019;Guo et al 2020;Pagliuso et al 2021). Thus, miRNA function may only be revealed under stressful or sensitized conditions (Brenner et al 2010).…”

“…2019), to mediate dietary restriction-induced longevity (Xu et al . 2019), and to protect the worm from graphene oxide toxicity in intestine (Guo et al . 2020).…”

“…Previous (Xu et al 2019), and to protect the worm from graphene oxide toxicity in intestine (Guo et al 2020). These miRNA functions may be independent of, or have an indirect connection to, the phenotypes we observe in sperm production.…”

An Intricate Network Involving the Argonaute ALG-1 Modulates Organismal Resistance to Oxidative Stress

“…miR-235-3p is also downregulated in aged worms, and mediates longevity induced by dietary restriction in C. elegans 64 . mir-235 also has a protective effect on the response to exposure to graphene oxide 65 , a toxic agent. These findings unveiled miRNAs induced by ALG-1 overexpression as relevant players in oxidative stress response.…”