The C. elegans neural editome reveals an ADAR target mRNA required for proper chemotaxis.
The C. elegans neural editome reveals an ADAR target mRNA required for proper chemotaxis.
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DOI：
10.7554/elife.28625
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发表时间：
2017-09-19
期刊：
影响因子：
7.7
通讯作者：
Hundley HA
中科院分区：
文献类型：
--
作者：
Deffit SN;Yee BA;Manning AC;Rajendren S;Vadlamani P;Wheeler EC;Domissy A;Washburn MC;Yeo GW;Hundley HA
ADAR proteins alter gene expression both by catalyzing adenosine (A) to inosine (I) RNA editing and binding to regulatory elements in target RNAs. Loss of ADARs affects neuronal function in all animals studied to date. Caenorhabditis elegans lacking ADARs exhibit reduced chemotaxis, but the targets responsible for this phenotype remain unknown. To identify critical neural ADAR targets in C. elegans, we performed an unbiased assessment of the effects of ADR-2, the only A-to-I editing enzyme in C. elegans, on the neural transcriptome. Development and implementation of publicly available software, SAILOR, identified 7361 A-to-I editing events across the neural transcriptome. Intersecting the neural editome with adr-2 associated gene expression changes, revealed an edited mRNA, clec-41, whose neural expression is dependent on deamination. Restoring clec-41 expression in adr-2 deficient neural cells rescued the chemotaxis defect, providing the first evidence that neuronal phenotypes of ADAR mutants can be caused by altered gene expression. DNA is the blueprint that tells each cell in an organism how it should operate. It encodes the instructions to make proteins and other molecules. To make a protein, a section of DNA known as a gene is used as a template to make molecules known as messenger ribonucleic acids (or mRNAs for short). The message in RNA consists of a series of individual letters, known as nucleotides, that tell the cell how much of a protein should be produced (referred to as gene expression) as well as the specific activities of each protein. The letters in mRNAs can be changed in specific cells and at certain points in development through a process known as RNA editing. This process is essential for animals to grow and develop normally and for the brain to work properly. Errors in RNA editing are found in patients suffering from a variety of neuropathological diseases, including Alzheimer’s disease, depression and brain tumors. Humans have millions of editing sites that are predicted to affect gene expression. However, many studies of RNA editing have only focused on the changes that alter protein activity. The ADAR proteins carry out a specific type of RNA editing in animals. In a microscopic worm known as Caenorhabditis elegans the loss of an ADAR protein called ADR-2 reduces the ability of the worm to move in response to chemicals, a process known as chemotaxis. Deffit et al. found that loss of ADR-2 affected the expression of over 150 genes in the nervous system of the worm. To identify which letters in the mRNAs were edited in the nervous system, Deffit et al. developed a new publically available software program called SAILOR (software for accurately identifying locations of RNA editing). This program can be used to detect RNA editing in any cell, tissue or organism. By combining the experimental and computational approaches, Deffit et al. were able to identify a gene that was edited in normal worms and expressed at lower levels in the mutant worms. Increasing the expression of just this one of gene in the mutant worms restored the worms’ ability to move towards a chemical “scent”. Together, these findings suggest that when studying human neuropathological diseases we should consider the effect of RNA editing on the amount of gene expression as well as protein activity. Future work should investigate the importance of RNA editing in controlling gene expression in other diseases including cancers.
