Tet-dependent 5-hydroxymethyl-Cytosine modification of mRNA regulates axon guidance genes in Drosophila.

Autor: Singh BN; Waksman Institute, Rutgers University, Piscataway, New Jersey, United States of America., Tran H; Waksman Institute, Rutgers University, Piscataway, New Jersey, United States of America., Kramer J; Department of Pathology and Laboratory Medicine, Rutgers Biomedical and Health Sciences, Rutgers University, New Brunswick, New Jersey, United States of America., Kirichenko E; Waksman Institute, Rutgers University, Piscataway, New Jersey, United States of America., Changela N; Waksman Institute, Rutgers University, Piscataway, New Jersey, United States of America., Wang F; Waksman Institute, Rutgers University, Piscataway, New Jersey, United States of America., Feng Y; Waksman Institute, Rutgers University, Piscataway, New Jersey, United States of America., Kumar D; Waksman Institute, Rutgers University, Piscataway, New Jersey, United States of America., Tu M; Waksman Institute, Rutgers University, Piscataway, New Jersey, United States of America., Lan J; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium., Bizet M; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium., Fuks F; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium., Steward R; Waksman Institute, Rutgers University, Piscataway, New Jersey, United States of America.; Department of Molecular Biology and Biochemistry, Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2024 Feb 21; Vol. 19 (2), pp. e0293894. Date of Electronic Publication: 2024 Feb 21 (Print Publication: 2024).
DOI: 10.1371/journal.pone.0293894
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Singh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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