We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine
Research Article

Genome-wide screening of altered m6A-tagged transcript profiles in the hippocampus after traumatic brain injury in mice

    Yiqin Wang

    CNRS-LIA Hematology and Cancer, Sino-French Research Center for Life Sciences & Genomics, State Key Laboratory of Medical Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, PR China

    Authors contributed equally

    Search for more papers by this author

    ,
    Jian Mao

    Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China

    Authors contributed equally

    Search for more papers by this author

    ,
    Xin Wang

    Department of Anesthesiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Pudong New District, Shanghai 200127, PR China

    Authors contributed equally

    Search for more papers by this author

    ,
    Yong Lin

    Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China

    ,
    Guoqiang Hou

    Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China

    ,
    Jun Zhu

    *Author for correspondence:

    E-mail Address: zhuj1966@yahoo.com

    CNRS-LIA Hematology and Cancer, Sino-French Research Center for Life Sciences & Genomics, State Key Laboratory of Medical Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, PR China

    &
    Baoshu Xie

    **Author for correspondence:

    E-mail Address: clairtree@163.com

    Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China

    Department of Neurosurgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong Province, PR China

    Published Online:https://doi.org/10.2217/epi-2019-0002

    Aim: To systematically profile RNA m6A modification landscape after traumatic brain injury (TBI) in mice. Materials & methods: Expression of m6A-related genes was detected by quantitative real-time PCR (qPCR). Expression and location of METTL3, a key component of m6A methyltransferase complex, were determined by immunostaining. Genome-wide profiling of m6A-tagged transcripts was conducted by m6A-modified RNA immunoprecipitation sequencing (m6A-RIP-seq) and RNA sequencing (RNA-seq). Results: METTL3 was downregulated after TBI. In total, 922 m6A peaks were differentially expressed as determined by m6A-RIP-seq, with 370 upregulated and 552 downregulated. In addition, we identified differentially expressed hypomethylated and hypermethylated mRNA transcripts. Conclusion: Our data provided novel information regarding m6A modification changes in the early period of TBI, which might be promising therapy targets.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 Brazinova A, Rehorcikova V, Taylor MS et al. Epidemiology of traumatic brain injury in Europe: a living systematic review. J. Neurotrauma doi:10.1089/neu.2015.4126 (2016) (Epub ahead of print).
    • 2 Majdan M, Plancikova D, Maas A et al. Years of life lost due to traumatic brain injury in Europe: a cross-sectional analysis of 16 countries. PLoS Med. 14(7), e1002331 (2017).
    • 3 Evans LP, Newell EA, Mahajan M et al. Acute vitreoretinal trauma and inflammation after traumatic brain injury in mice. Ann. Clin. Transl. Neurol. 5(3), 240–251 (2018).
    • 4 Cheng P, Yin P, Ning P et al. Trends in traumatic brain injury mortality in China, 2006–2013: a population-based longitudinal study. PLoS Med. 14(7), e1002332 (2017).
    • 5 Mcginn MJ, Povlishock JT. Pathophysiology of traumatic brain injury. Neurosurg. Clin. N. Am. 27(4), 397–407 (2016).
    • 6 Li W, Wang X, Wei X, Wang M. Susceptibility-weighted and diffusion kurtosis imaging to evaluate encephalomalacia with epilepsy after traumatic brain injury. Ann. Clin. Transl. Neurol. 5(5), 552–558 (2018).
    • 7 Wang CF, Zhao CC, Weng WJ et al. Alteration in long non-coding RNA expression after traumatic brain injury in rats. J. Neurotrauma 34(13), 2100–2108 (2017).
    • 8 Xie BS, Wang YQ, Lin Y et al. Circular RNA expression profiles alter significantly after traumatic brain injury in rats. J. Neurotrauma 35(14), 1659–1666 (2018).
    • 9 Weng YL, Wang X, An R et al. Epitranscriptomic m(6)A regulation of axon regeneration in the adult mammalian nervous system. Neuron 97(2), 313–325 (2018).
    • 10 Wei J, Liu F, Lu Z et al. Differential m 6A, m6Am, and m1A demethylation mediated by FTO in the cell nucleus and cytoplasm. Mol. cell 71(6), 973–985 (2018).
    • 11 Hibar DP, Stein JL, Renteria ME et al. Common genetic variants influence human subcortical brain structures. Nature 520(7546), 224–229 (2015).
    • 12 Meyer KD, Jaffrey SR. Rethinking m(6)A readers, writers, and erasers. Ann. Rev. Cell Dev. Biol. 33, 319–342 (2017).
    • 13 Li F, Kennedy S, Hajian T et al. A radioactivity-based assay for screening human m6A-RNA methyltransferase, METTL3-METTL14 complex, and demethylase ALKBH5. J. Biomol. Screen. 21(3), 290–297 (2016).
    • 14 Golovina AY, Dzama MM, Petriukov KS et al. Method for site-specific detection of m6A nucleoside presence in RNA based on high-resolution melting (HRM) analysis. Nucleic Acids Res. 42(4), e27 (2014).
    • 15 Lence T, Akhtar J, Bayer M et al. m(6)A modulates neuronal functions and sex determination in Drosophila. Nature 540(7632), 242–247 (2016). • Describe the crucial functions of m6A modification in fundamental processes.
    • 16 Zhou J, Wan J, Shu XE et al. N(6)-Methyladenosine guides mRNA alternative translation during integrated stress response. Mol. cell 69(4), 636–647 (2018). • Describes the role of m6A methylation in stress response.
    • 17 Wen J, Lv R, Ma H et al. Zc3h13 regulates nuclear RNA m(6)A methylation and mouse embryonic stem cell self-renewal. Mol. cell 69(6), 1028–1038 (2018).
    • 18 Wang H, Zuo H, Liu J et al. Loss of YTHDF2-mediated m(6)A-dependent mRNA clearance facilitates hematopoietic stem cell regeneration. Cell Res. 28(10), 1035–1038 (2018).
    • 19 Tong J, Flavell RA, Li HB. RNA m(6)A modification and its function in diseases. Front. Med. 12(4), 481–489 (2018).
    • 20 Xie BS, Wang YQ, Lin Y et al. Inhibition of ferroptosis attenuates tissue damage and improves long-term outcomes after traumatic brain injury in mice. CNS Neurosci. Ther. 25(4), 465–475 (2018).
    • 21 Zhao X, Chen Y, Mao Q et al. Overexpression of YTHDF1 is associated with poor prognosis in patients with hepatocellular carcinoma. Cancer Biomark. 21(4), 859–868 (2018).
    • 22 Yang Y, Shen F, Huang W et al. Glucose is involved in the dynamic regulation of m6A in patients with Type 2 diabetes. J. Clin. Endocrinol. Metabolism 104(3), 665–673 (2018).
    • 23 Vu LP, Pickering BF, Cheng Y et al. The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat. Med. 23(11), 1369–1376 (2017).
    • 24 Mathiyalagan P, Adamiak M, Mayourian J et al. FTO-dependent m6A regulates cardiac function during remodeling and repair. Circulation 139(4), 518–532 (2018).
    • 25 Scholler E, Weichmann F, Treiber T et al. Interactions, localization, and phosphorylation of the m(6)A generating METTL3-METTL14-WTAP complex. RNA 24(4), 499–512 (2018).
    • 26 Zhao X, Yang Y, Sun BF et al. FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Res. 24(12), 1403–1419 (2014).
    • 27 Chen M, Wei L, Law CT et al. RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2. Hepatology 67(6), 2254–2270 (2018).
    • 28 Visvanathan A, Patil V, Arora A et al. Essential role of METTL3-mediated m(6)A modification in glioma stem-like cells maintenance and radioresistance. Oncogene 37(4), 522–533 (2018).
    • 29 Li X, Tang J, Huang W et al. The M6A methyltransferase METTL3: acting as a tumor suppressor in renal cell carcinoma. Oncotarget 8(56), 96103–96116 (2017).
    • 30 Wang CX, Cui GS, Liu X et al. METTL3-mediated m6A modification is required for cerebellar development. PLoS Biol. 16(6), e2004880 (2018).
    • 31 Shi H, Zhang X, Weng YL et al. m(6)A facilitates hippocampus-dependent learning and memory through YTHDF1. Nature 563(7730), 249–253 (2018). •• Describes the role of m6A-methylated neuronal mRNAs in learning and memory.
    • 32 Ke S, Pandya-Jones A, Saito Y et al. m(6)A mRNA modifications are deposited in nascent pre-mRNA and are not required for splicing but do specify cytoplasmic turnover. Genes Dev. 31(10), 990–1006 (2017).
    • 33 Du Y, Hou G, Zhang H et al. SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function. Nucleic Acids Res. 46(10), 5195–5208 (2018).
    • 34 Vespa P, Tubi M, Claassen J et al. Metabolic crisis occurs with seizures and periodic discharges after brain trauma. Ann. Neurol. 79(4), 579–590 (2016).
    • 35 Mckenna MC, Scafidi S, Robertson CL. Metabolic alterations in developing brain after injury: knowns and unknowns. Neurochem. Res. 40(12), 2527–2543 (2015).
    • 36 Prins ML, Matsumoto J. Metabolic response of pediatric traumatic brain injury. J. Child Neurol.. 31(1), 28–34 (2016).
    • 37 Chang M, Lv H, Zhang W et al. Region-specific RNA m(6)A methylation represents a new layer of control in the gene regulatory network in the mouse brain. Open Biol. 7(9), (2017).
    • 38 Yue Y, Liu J, He C. RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation. Genes Dev. 29(13), 1343–1355 (2015).
    • 39 Zhao BS, Roundtree IA, He C. Post-transcriptional gene regulation by mRNA modifications. Nat. Rev. Mol. Cell Biol. 18(1), 31–42 (2017).
    • 40 Zhao BS, He C. ‘Gamete On’ for m(6)A: YTHDF2 exerts essential functions in female fertility. Mol. cell 67(6), 903–905 (2017).
    • 41 Li M, Zhao X, Wang W et al. Ythdf2-mediated m(6)A mRNA clearance modulates neural development in mice. Genome Biol. 19(1), 69 (2018).
    • 42 Li A, Chen YS, Ping XL et al. Cytoplasmic m(6)A reader YTHDF3 promotes mRNA translation. Cell Res. 27(3), 444–447 (2017).