Distinct roles of Fto and Mettl3 in controlling development of the cerebral cortex through transcriptional and translational regulations

Abstract Proper development of the mammalian cerebral cortex relies on precise gene expression regulation, which is controlled by genetic, epigenetic, and epitranscriptomic factors. Here we generate RNA demethylase Fto and methyltransferase Mettl3 cortical-specific conditional knockout mice, and det...

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Main Authors: Kunzhao Du, Zhen Zhang, Zhiwei Zeng, Jinling Tang, Trevor Lee, Tao Sun
Format: Article
Language:English
Published: Nature Publishing Group 2021-07-01
Series:Cell Death and Disease
Online Access:https://doi.org/10.1038/s41419-021-03992-2
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spelling doaj-647add9362d44edfaa25f31ec6c585132021-07-18T11:04:58ZengNature Publishing GroupCell Death and Disease2041-48892021-07-0112711210.1038/s41419-021-03992-2Distinct roles of Fto and Mettl3 in controlling development of the cerebral cortex through transcriptional and translational regulationsKunzhao Du0Zhen Zhang1Zhiwei Zeng2Jinling Tang3Trevor Lee4Tao Sun5Center for Precision Medicine, School of Medicine and School of Biomedical Sciences, Huaqiao UniversitySchool of Life Sciences and Biotechnology, Shanghai Jiao Tong UniversityCenter for Precision Medicine, School of Medicine and School of Biomedical Sciences, Huaqiao UniversityCenter for Precision Medicine, School of Medicine and School of Biomedical Sciences, Huaqiao UniversityDepartment of Cell and Developmental Biology, Cornell University Weill Medical CollegeCenter for Precision Medicine, School of Medicine and School of Biomedical Sciences, Huaqiao UniversityAbstract Proper development of the mammalian cerebral cortex relies on precise gene expression regulation, which is controlled by genetic, epigenetic, and epitranscriptomic factors. Here we generate RNA demethylase Fto and methyltransferase Mettl3 cortical-specific conditional knockout mice, and detect severe brain defects caused by Mettl3 deletion but not Fto knockout. Transcriptomic profiles using RNA sequencing indicate that knockout of Mettl3 causes a more dramatic alteration on gene transcription than that of Fto. Interestingly, we conduct ribosome profiling sequencing, and find that knockout of Mettl3 leads to a more severe disruption of translational regulation of mRNAs than deletion of Fto and results in altered translation of crucial genes in cortical radial glial cells and intermediate progenitors. Moreover, Mettl3 deletion causes elevated translation of a significant number of mRNAs, in particular major components in m6A methylation. Our findings indicate distinct functions of Mettl3 and Fto in brain development, and uncover a profound role of Mettl3 in regulating translation of major mRNAs that control proper cortical development.https://doi.org/10.1038/s41419-021-03992-2
collection DOAJ
language English
format Article
sources DOAJ
author Kunzhao Du
Zhen Zhang
Zhiwei Zeng
Jinling Tang
Trevor Lee
Tao Sun
spellingShingle Kunzhao Du
Zhen Zhang
Zhiwei Zeng
Jinling Tang
Trevor Lee
Tao Sun
Distinct roles of Fto and Mettl3 in controlling development of the cerebral cortex through transcriptional and translational regulations
Cell Death and Disease
author_facet Kunzhao Du
Zhen Zhang
Zhiwei Zeng
Jinling Tang
Trevor Lee
Tao Sun
author_sort Kunzhao Du
title Distinct roles of Fto and Mettl3 in controlling development of the cerebral cortex through transcriptional and translational regulations
title_short Distinct roles of Fto and Mettl3 in controlling development of the cerebral cortex through transcriptional and translational regulations
title_full Distinct roles of Fto and Mettl3 in controlling development of the cerebral cortex through transcriptional and translational regulations
title_fullStr Distinct roles of Fto and Mettl3 in controlling development of the cerebral cortex through transcriptional and translational regulations
title_full_unstemmed Distinct roles of Fto and Mettl3 in controlling development of the cerebral cortex through transcriptional and translational regulations
title_sort distinct roles of fto and mettl3 in controlling development of the cerebral cortex through transcriptional and translational regulations
publisher Nature Publishing Group
series Cell Death and Disease
issn 2041-4889
publishDate 2021-07-01
description Abstract Proper development of the mammalian cerebral cortex relies on precise gene expression regulation, which is controlled by genetic, epigenetic, and epitranscriptomic factors. Here we generate RNA demethylase Fto and methyltransferase Mettl3 cortical-specific conditional knockout mice, and detect severe brain defects caused by Mettl3 deletion but not Fto knockout. Transcriptomic profiles using RNA sequencing indicate that knockout of Mettl3 causes a more dramatic alteration on gene transcription than that of Fto. Interestingly, we conduct ribosome profiling sequencing, and find that knockout of Mettl3 leads to a more severe disruption of translational regulation of mRNAs than deletion of Fto and results in altered translation of crucial genes in cortical radial glial cells and intermediate progenitors. Moreover, Mettl3 deletion causes elevated translation of a significant number of mRNAs, in particular major components in m6A methylation. Our findings indicate distinct functions of Mettl3 and Fto in brain development, and uncover a profound role of Mettl3 in regulating translation of major mRNAs that control proper cortical development.
url https://doi.org/10.1038/s41419-021-03992-2
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