Tet-dependent 5-hydroxymethyl-Cytosine modification of mRNA regulates axon guidance genes in Drosophila.
Modifications of mRNA, especially methylation of adenosine, have recently drawn much attention. The much rarer modification, 5-hydroxymethylation of cytosine (5hmC), is not well understood and is the subject of this study. Vertebrate Tet proteins are 5-methylcytosine (5mC) hydroxylases and catalyze...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2024-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0293894 |
| _version_ | 1797266342565380096 |
|---|---|
| author | Badri Nath Singh Hiep Tran Joseph Kramer Elmira Kirichenko Neha Changela Fei Wang Yaping Feng Dibyendu Kumar Min Tu Jie Lan Martin Bizet François Fuks Ruth Steward |
| author_facet | Badri Nath Singh Hiep Tran Joseph Kramer Elmira Kirichenko Neha Changela Fei Wang Yaping Feng Dibyendu Kumar Min Tu Jie Lan Martin Bizet François Fuks Ruth Steward |
| author_sort | Badri Nath Singh |
| collection | DOAJ |
| description | Modifications of mRNA, especially methylation of adenosine, have recently drawn much attention. The much rarer modification, 5-hydroxymethylation of cytosine (5hmC), is not well understood and is the subject of this study. Vertebrate Tet proteins are 5-methylcytosine (5mC) hydroxylases and catalyze the transition of 5mC to 5hmC in DNA. These enzymes have recently been shown to have the same function in messenger RNAs in both vertebrates and in Drosophila. The Tet gene is essential in Drosophila as Tet knock-out animals do not reach adulthood. We describe the identification of Tet-target genes in the embryo and larval brain by mapping one, Tet DNA-binding sites throughout the genome and two, the Tet-dependent 5hmrC modifications transcriptome-wide. 5hmrC modifications are distributed along the entire transcript, while Tet DNA-binding sites are preferentially located at the promoter where they overlap with histone H3K4me3 peaks. The identified mRNAs are preferentially involved in neuron and axon development and Tet knock-out led to a reduction of 5hmrC marks on specific mRNAs. Among the Tet-target genes were the robo2 receptor and its slit ligand that function in axon guidance in Drosophila and in vertebrates. Tet knock-out embryos show overlapping phenotypes with robo2 and both Robo2 and Slit protein levels were markedly reduced in Tet KO larval brains. Our results establish a role for Tet-dependent 5hmrC in facilitating the translation of modified mRNAs primarily in cells of the nervous system. |
| first_indexed | 2024-03-07T19:40:28Z |
| format | Article |
| id | doaj.art-3ce50553810e4b2e8cb5a9fbd4184a4f |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-25T00:59:10Z |
| publishDate | 2024-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-3ce50553810e4b2e8cb5a9fbd4184a4f2024-03-11T05:32:26ZengPublic Library of Science (PLoS)PLoS ONE1932-62032024-01-01192e029389410.1371/journal.pone.0293894Tet-dependent 5-hydroxymethyl-Cytosine modification of mRNA regulates axon guidance genes in Drosophila.Badri Nath SinghHiep TranJoseph KramerElmira KirichenkoNeha ChangelaFei WangYaping FengDibyendu KumarMin TuJie LanMartin BizetFrançois FuksRuth StewardModifications of mRNA, especially methylation of adenosine, have recently drawn much attention. The much rarer modification, 5-hydroxymethylation of cytosine (5hmC), is not well understood and is the subject of this study. Vertebrate Tet proteins are 5-methylcytosine (5mC) hydroxylases and catalyze the transition of 5mC to 5hmC in DNA. These enzymes have recently been shown to have the same function in messenger RNAs in both vertebrates and in Drosophila. The Tet gene is essential in Drosophila as Tet knock-out animals do not reach adulthood. We describe the identification of Tet-target genes in the embryo and larval brain by mapping one, Tet DNA-binding sites throughout the genome and two, the Tet-dependent 5hmrC modifications transcriptome-wide. 5hmrC modifications are distributed along the entire transcript, while Tet DNA-binding sites are preferentially located at the promoter where they overlap with histone H3K4me3 peaks. The identified mRNAs are preferentially involved in neuron and axon development and Tet knock-out led to a reduction of 5hmrC marks on specific mRNAs. Among the Tet-target genes were the robo2 receptor and its slit ligand that function in axon guidance in Drosophila and in vertebrates. Tet knock-out embryos show overlapping phenotypes with robo2 and both Robo2 and Slit protein levels were markedly reduced in Tet KO larval brains. Our results establish a role for Tet-dependent 5hmrC in facilitating the translation of modified mRNAs primarily in cells of the nervous system.https://doi.org/10.1371/journal.pone.0293894 |
| spellingShingle | Badri Nath Singh Hiep Tran Joseph Kramer Elmira Kirichenko Neha Changela Fei Wang Yaping Feng Dibyendu Kumar Min Tu Jie Lan Martin Bizet François Fuks Ruth Steward Tet-dependent 5-hydroxymethyl-Cytosine modification of mRNA regulates axon guidance genes in Drosophila. PLoS ONE |
| title | Tet-dependent 5-hydroxymethyl-Cytosine modification of mRNA regulates axon guidance genes in Drosophila. |
| title_full | Tet-dependent 5-hydroxymethyl-Cytosine modification of mRNA regulates axon guidance genes in Drosophila. |
| title_fullStr | Tet-dependent 5-hydroxymethyl-Cytosine modification of mRNA regulates axon guidance genes in Drosophila. |
| title_full_unstemmed | Tet-dependent 5-hydroxymethyl-Cytosine modification of mRNA regulates axon guidance genes in Drosophila. |
| title_short | Tet-dependent 5-hydroxymethyl-Cytosine modification of mRNA regulates axon guidance genes in Drosophila. |
| title_sort | tet dependent 5 hydroxymethyl cytosine modification of mrna regulates axon guidance genes in drosophila |
| url | https://doi.org/10.1371/journal.pone.0293894 |
| work_keys_str_mv | AT badrinathsingh tetdependent5hydroxymethylcytosinemodificationofmrnaregulatesaxonguidancegenesindrosophila AT hieptran tetdependent5hydroxymethylcytosinemodificationofmrnaregulatesaxonguidancegenesindrosophila AT josephkramer tetdependent5hydroxymethylcytosinemodificationofmrnaregulatesaxonguidancegenesindrosophila AT elmirakirichenko tetdependent5hydroxymethylcytosinemodificationofmrnaregulatesaxonguidancegenesindrosophila AT nehachangela tetdependent5hydroxymethylcytosinemodificationofmrnaregulatesaxonguidancegenesindrosophila AT feiwang tetdependent5hydroxymethylcytosinemodificationofmrnaregulatesaxonguidancegenesindrosophila AT yapingfeng tetdependent5hydroxymethylcytosinemodificationofmrnaregulatesaxonguidancegenesindrosophila AT dibyendukumar tetdependent5hydroxymethylcytosinemodificationofmrnaregulatesaxonguidancegenesindrosophila AT mintu tetdependent5hydroxymethylcytosinemodificationofmrnaregulatesaxonguidancegenesindrosophila AT jielan tetdependent5hydroxymethylcytosinemodificationofmrnaregulatesaxonguidancegenesindrosophila AT martinbizet tetdependent5hydroxymethylcytosinemodificationofmrnaregulatesaxonguidancegenesindrosophila AT francoisfuks tetdependent5hydroxymethylcytosinemodificationofmrnaregulatesaxonguidancegenesindrosophila AT ruthsteward tetdependent5hydroxymethylcytosinemodificationofmrnaregulatesaxonguidancegenesindrosophila |