Effective axonal regeneration in the adult mammalian nervous system requires coordination of elevated intrinsic growth capacity and decreased responses to the inhibitory environment. Intrinsic regenerative capacity largely depends on the gene regulatory network and protein translation machinery. A failure to activate these pathways upon injury is underlying a lack of robust axon regeneration in the mature mammalian central nervous system. Epigenetics and epitranscriptomics are key regulatory mechanisms that shape gene expression and protein translation. Here, we provide an overview of different types of modifications on DNA, histones, and RNA, underpinning the regenerative competence of axons in the mature mammalian peripheral and central nervous systems. We highlight other non-neuronal cells and their epigenetic changes in determining the microenvironment for tissue repair and axon regeneration. We also address advancements of single-cell technology in charting transcriptomic and epigenetic landscapes that may further facilitate the mechanistic understanding of differential regenerative capacity in neuronal subtypes. Finally, as epigenetic and epitranscriptomic processes are commonly affected by brain injuries and psychiatric disorders, understanding their alterations upon brain injury would provide unprecedented mechanistic insights into etiology of injury-associated-psychiatric disorders and facilitate the development of therapeutic interventions to restore brain function.
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Goldberg JL, Klassen MP, Hua Y, Barres BA. Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells. Science. 2002;296:1860–4.
Blackmore M, Letourneau PC. Changes within maturing neurons limit axonal regeneration in the developing spinal cord. J Neurobiol. 2006;66:348–60.
Park KK, Liu K, Hu Y, Smith PD, Wang C, Cai B, et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science. 2008;322:963–6.
Smith PD, Sun F, Park KK, Cai B, Wang C, Kuwako K, et al. SOCS3 deletion promotes optic nerve regeneration in vivo. Neuron. 2009;64:617–23.
Cho Y, Sloutsky R, Naegle KM, Cavalli V. Injury-induced HDAC5 nuclear export is essential for axon regeneration. Cell. 2013;155:894–908.
Tedeschi A, Dupraz S, Laskowski CJ, Xue J, Ulas T, Beyer M, et al. The calcium channel subunit Alpha2delta2 suppresses axon regeneration in the adult CNS. Neuron. 2016;92:419–34.
Chandran V, Coppola G, Nawabi H, Omura T, Versano R, Huebner EA, et al. A systems-level analysis of the peripheral nerve intrinsic axonal growth program. Neuron. 2016;89:956–70.
Yang C, Wang X, Wang J, Wang X, Chen W, Lu N, et al. Rewiring neuronal glycerolipid metabolism determines the extent of axon regeneration. Neuron. 2020;105:276–92.e275.
Yiu G, He Z. Glial inhibition of CNS axon regeneration. Nat Rev Neurosci. 2006;7:617–27.
Avraham O, Deng PY, Jones S, Kuruvilla R, Semenkovich CF, Klyachko VA, et al. Satellite glial cells promote regenerative growth in sensory neurons. Nat Commun. 2020;11:4891.
Bellver-Landete V, Bretheau F, Mailhot B, Vallieres N, Lessard M, Janelle ME, et al. Microglia are an essential component of the neuroprotective scar that forms after spinal cord injury. Nat Commun. 2019;10:518.
Feng Y, Peng Y, Jie J, Yang Y, Yang P. The immune microenvironment and tissue engineering strategies for spinal cord regeneration. Front Cell Neurosci. 2022;16:969002.
Sas AR, Carbajal KS, Jerome AD, Menon R, Yoon C, Kalinski AL, et al. A new neutrophil subset promotes CNS neuron survival and axon regeneration. Nat Immunol. 2020;21:1496–505.
Silver J, Miller JH. Regeneration beyond the glial scar. Nat Rev Neurosci. 2004;5:146–56.
Anderson MA, Burda JE, Ren Y, Ao Y, O’Shea TM, Kawaguchi R, et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature. 2016;532:195–200.
Duan X, Qiao M, Bei F, Kim IJ, He Z, Sanes JR. Subtype-specific regeneration of retinal ganglion cells following axotomy: effects of osteopontin and mTOR signaling. Neuron. 2015;85:1244–56.
Vissers C, Sinha A, Ming GL, Song H. The epitranscriptome in stem cell biology and neural development. Neurobiol Dis. 2020;146:105139.
Yoon KJ, Vissers C, Ming GL, Song H. Epigenetics and epitranscriptomics in temporal patterning of cortical neural progenitor competence. J Cell Biol. 2018;217:1901–14.
Fujita Y, Pather SR, Ming GL, Song H. 3D spatial genome organization in the nervous system: From development and plasticity to disease. Neuron. 2022;110:2902–15.
Starnawska A, Demontis D. Role of DNA methylation in mediating genetic risk of psychiatric disorders. Front Psychiatry. 2021;12:596821.
Tsankova N, Renthal W, Kumar A, Nestler EJ. Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci. 2007;8:355–67.
Engel M, Eggert C, Kaplick PM, Eder M, Roh S, Tietze L, et al. The role of m(6)A/m-RNA methylation in stress response regulation. Neuron. 2018;99:389–403.e389.
van Reekum R, Cohen T, Wong J. Can traumatic brain injury cause psychiatric disorders? J Neuropsychiatry Clin Neurosci. 2000;12:316–27.
Niu J, Wang B, Wang T, Zhou T. Mechanism of METTL3-mediated m6A modification in depression-induced cognitive deficits. Am J Med Genet B Neuropsychiatr Genet. 2022;189:86–99.
Dong E, Gavin DP, Chen Y, Davis J. Upregulation of TET1 and downregulation of APOBEC3A and APOBEC3C in the parietal cortex of psychotic patients. Transl Psychiatry. 2012;2:e159.
Antunes C, Da Silva JD, Guerra-Gomes S, Alves ND, Ferreira F, Loureiro-Campos E, et al. Tet3 ablation in adult brain neurons increases anxiety-like behavior and regulates cognitive function in mice. Mol Psychiatry. 2021;26:1445–57.
Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci. 2006;9:519–25.
Bahari-Javan S, Varbanov H, Halder R, Benito E, Kaurani L, Burkhardt S, et al. HDAC1 links early life stress to schizophrenia-like phenotypes. Proc Natl Acad Sci USA. 2017;114:E4686–94.
Grippo P, Iaccarino M, Parisi E, Scarano E. Methylation of DNA in developing sea urchin embryos. J Mol Biol. 1968;36:195–208.
Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009;462:315–22.
Guo JU, Su Y, Shin JH, Shin J, Li H, Xie B, et al. Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. Nat Neurosci. 2014;17:215–22.
Breiling A, Lyko F. Epigenetic regulatory functions of DNA modifications: 5-methylcytosine and beyond. Epigenetics Chromatin. 2015;8:24.
Cedar H, Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet. 2009;10:295–304.
Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99:247–57.
Probst AV, Dunleavy E, Almouzni G. Epigenetic inheritance during the cell cycle. Nat Rev Mol Cell Biol. 2009;10:192–206.
He Y, Ecker JR. Non-CG methylation in the human genome. Annu Rev Genomics Hum Genet. 2015;16:55–77.
Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23:185–8.
Della Ragione F, Vacca M, Fioriniello S, Pepe G, D’Esposito M. MECP2, a multi-talented modulator of chromatin architecture. Brief Funct Genomics. 2016;15:420–31.
Kinde B, Gabel HW, Gilbert CS, Griffith EC, Greenberg ME. Reading the unique DNA methylation landscape of the brain: Non-CpG methylation, hydroxymethylation, and MeCP2. Proc Natl Acad Sci USA. 2015;112:6800–6.
Sharifi O, Yasui DH. The molecular functions of MeCP2 in Rett syndrome pathology. Front Genet. 2021;12:624290.
Young JI, Hong EP, Castle JC, Crespo-Barreto J, Bowman AB, Rose MF, et al. Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2. Proc Natl Acad Sci USA. 2005;102:17551–8.
Chen L, Chen K, Lavery LA, Baker SA, Shaw CA, Li W, et al. MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome. Proc Natl Acad Sci USA. 2015;112:5509–14.
Perzel Mandell KA, Price AJ, Wilton R, Collado-Torres L, Tao R, Eagles NJ, et al. Characterizing the dynamic and functional DNA methylation landscape in the developing human cortex. Epigenetics. 2021;16:1–13.
Ellis SE, Gupta S, Moes A, West AB, Arking DE. Exaggerated CpH methylation in the autism-affected brain. Mol Autism. 2017;8:6.
Gabel HW, Kinde B, Stroud H, Gilbert CS, Harmin DA, Kastan NR, et al. Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. Nature. 2015;522:89–93.
Lister R, Mukamel EA, Nery JR, Urich M, Puddifoot CA, Johnson ND, et al. Global epigenomic reconfiguration during mammalian brain development. Science. 2013;341:1237905.
Kass SU, Pruss D, Wolffe AP. How does DNA methylation repress transcription? Trends Genet. 1997;13:444–9.
Siegfried Z, Eden S, Mendelsohn M, Feng X, Tsuberi BZ, Cedar H. DNA methylation represses transcription in vivo. Nat Genet. 1999;22:203–6.
Yin Y, Morgunova E, Jolma A, Kaasinen E, Sahu B, Khund-Sayeed S, et al. Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science. 2017;356:eaaj2239.
Hu S, Wan J, Su Y, Song Q, Zeng Y, Nguyen HN, et al. DNA methylation presents distinct binding sites for human transcription factors. eLife. 2013;2:e00726.
Heberle E, Bardet AF. Sensitivity of transcription factors to DNA methylation. Essays Biochem. 2019;63:727–41.
Schultz MD, He Y, Whitaker JW, Hariharan M, Mukamel EA, Leung D, et al. Human body epigenome maps reveal noncanonical DNA methylation variation. Nature. 2015;523:212–6.
Ziller MJ, Gu H, Muller F, Donaghey J, Tsai LT, Kohlbacher O, et al. Charting a dynamic DNA methylation landscape of the human genome. Nature. 2013;500:477–81.
Morselli M, Pastor WA, Montanini B, Nee K, Ferrari R, Fu K, et al. In vivo targeting of de novo DNA methylation by histone modifications in yeast and mouse. Elife. 2015;4:e06205.
Wu H, Coskun V, Tao J, Xie W, Ge W, Yoshikawa K, et al. Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science. 2010;329:444–8.
Cholewa-Waclaw J, Shah R, Webb S, Chhatbar K, Ramsahoye B, Pusch O, et al. Quantitative modelling predicts the impact of DNA methylation on RNA polymerase II traffic. Proc Natl Acad Sci USA. 2019;116:14995–15000.
Luo C, Hajkova P, Ecker JR. Dynamic DNA methylation: In the right place at the right time. Science. 2018;361:1336–40.
Guo JU, Su Y, Zhong C, Ming GL, Song H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell. 2011;145:423–34.
He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q, et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science. 2011;333:1303–7.
Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010;466:1129–33.
Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science. 2011;333:1300–3.
Wu X, Zhang Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat Rev Genet. 2017;18:517–34.
Cui XL, Nie J, Ku J, Dougherty U, West-Szymanski DC, Collin F, et al. A human tissue map of 5-hydroxymethylcytosines exhibits tissue specificity through gene and enhancer modulation. Nat Commun. 2020;11:6161.
He B, Zhang C, Zhang X, Fan Y, Zeng H, Liu J, et al. Tissue-specific 5-hydroxymethylcytosine landscape of the human genome. Nat Commun. 2021;12:4249.
Hahn MA, Qiu R, Wu X, Li AX, Zhang H, Wang J, et al. Dynamics of 5-hydroxymethylcytosine and chromatin marks in Mammalian neurogenesis. Cell Rep. 2013;3:291–300.
Mellen M, Ayata P, Heintz N. 5-hydroxymethylcytosine accumulation in postmitotic neurons results in functional demethylation of expressed genes. Proc Natl Acad Sci USA. 2017;114:E7812–E7821.
Tan L, Xiong L, Xu W, Wu F, Huang N, Xu Y, et al. Genome-wide comparison of DNA hydroxymethylation in mouse embryonic stem cells and neural progenitor cells by a new comparative hMeDIP-seq method. Nucleic Acids Res. 2013;41:e84.
Gontier G, Iyer M, Shea JM, Bieri G, Wheatley EG, Ramalho-Santos M, et al. Tet2 rescues age-related regenerative decline and enhances cognitive function in the adult mouse brain. Cell Rep. 2018;22:1974–81.
van den Oord C, Copeland WE, Zhao M, Xie LY, Aberg KA, van den Oord E. DNA methylation signatures of childhood trauma predict psychiatric disorders and other adverse outcomes 17 years after exposure. Mol Psychiatry. 2022;27:3367–73.
Muller D, Grevet EH, Figueira da Silva NA, Bandeira CE, Barbosa E, Vitola ES, et al. Global DNA methylation changes in adults with attention deficit-hyperactivity disorder and its comorbidity with bipolar disorder: links with polygenic scores. Mol Psychiatry. 2022;27:2485–91.
Bundo M, Ueda J, Nakachi Y, Kasai K, Kato T, Iwamoto K. Decreased DNA methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder. Mol Psychiatry. 2021;26:3407–18.
Cheng Y, Li Z, Manupipatpong S, Lin L, Li X, Xu T, et al. 5-Hydroxymethylcytosine alterations in the human postmortem brains of autism spectrum disorder. Hum Mol Genet. 2018;27:2955–64.
Golzenleuchter M, Kanwar R, Zaibak M, Al Saiegh F, Hartung T, Klukas J, et al. Plasticity of DNA methylation in a nerve injury model of pain. Epigenetics. 2015;10:200–12.
Garriga J, Laumet G, Chen SR, Zhang Y, Madzo J, Issa JJ, et al. Nerve injury-induced chronic pain is associated with persistent DNA methylation reprogramming in dorsal root ganglion. J Neurosci. 2018;38:6090–101.
Iskandar BJ, Rizk E, Meier B, Hariharan N, Bottiglieri T, Finnell RH, et al. Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation. J Clin Investig. 2010;120:1603–16.
Madrid A, Borth LE, Hogan KJ, Hariharan N, Papale LA, Alisch RS, et al. DNA methylation and hydroxymethylation have distinct genome-wide profiles related to axonal regeneration. Epigenetics. 2021;16:64–78.
Oh YM, Mahar M, Ewan EE, Leahy KM, Zhao G, Cavalli V. Epigenetic regulator UHRF1 inactivates REST and growth suppressor gene expression via DNA methylation to promote axon regeneration. Proc Natl Acad Sci USA. 2018;115:E12417–26.
Li H, Rauch T, Chen ZX, Szabo PE, Riggs AD, Pfeifer GP. The histone methyltransferase SETDB1 and the DNA methyltransferase DNMT3A interact directly and localize to promoters silenced in cancer cells. J Biol Chem. 2006;281:19489–500.
Rajavelu A, Lungu C, Emperle M, Dukatz M, Brohm A, Broche J, et al. Chromatin-dependent allosteric regulation of DNMT3A activity by MeCP2. Nucleic Acids Res. 2018;46:9044–56.
Loh YE, Koemeter-Cox A, Finelli MJ, Shen L, Friedel RH, Zou H. Comprehensive mapping of 5-hydroxymethylcytosine epigenetic dynamics in axon regeneration. Epigenetics. 2017;12:77–92.
Weng YL, An R, Cassin J, Joseph J, Mi R, Wang C, et al. An intrinsic epigenetic barrier for functional axon regeneration. Neuron. 2017;94:337–346.e336.
Liu XS, Jaenisch R. Editing the epigenome to tackle brain disorders. Trends Neurosci. 2019;42:861–70.
Thakore PI, Black JB, Hilton IB, Gersbach CA. Editing the epigenome: technologies for programmable transcription and epigenetic modulation. Nat Methods. 2016;13:127–37.
Hilton IB, D’Ippolito AM, Vockley CM, Thakore PI, Crawford GE, Reddy TE, et al. Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat Biotechnol. 2015;33:510–7.
Liu XS, Wu H, Ji X, Stelzer Y, Wu X, Czauderna S, et al. Editing DNA methylation in the mammalian genome. Cell. 2016;167:233–47.e217.
Liu XS, Wu H, Krzisch M, Wu X, Graef J, Muffat J, et al. Rescue of fragile X syndrome neurons by DNA methylation editing of the FMR1 Gene. Cell. 2018;172:979–92.e976.
Gasperini M, Hill AJ, McFaline-Figueroa JL, Martin B, Kim S, Zhang MD, et al. A genome-wide framework for mapping gene regulation via cellular genetic screens. Cell. 2019;176:377–90.e319.
Creyghton MP, Cheng AW, Welstead GG, Kooistra T, Carey BW, Steine EJ, et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci USA. 2010;107:21931–6.
Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, et al. High-resolution profiling of histone methylations in the human genome. Cell. 2007;129:823–37.
Padeken J, Methot SP, Gasser SM. Establishment of H3K9-methylated heterochromatin and its functions in tissue differentiation and maintenance. Nat Rev Mol Cell Biol. 2022;23:623–40.
Sun H, Kennedy PJ, Nestler EJ. Epigenetics of the depressed brain: role of histone acetylation and methylation. Neuropsychopharmacology. 2013;38:124–37.
Kishi T, Yoshimura R, Kitajima T, Okochi T, Okumura T, Tsunoka T, et al. SIRT1 gene is associated with major depressive disorder in the Japanese population. J Affect Disord. 2010;126:167–73.
Puttagunta R, Tedeschi A, Soria MG, Hervera A, Lindner R, Rathore KI, et al. PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system. Nat Commun. 2014;5:3527.
Lv L, Han X, Sun Y, Wang X, Dong Q. Valproic acid improves locomotion in vivo after SCI and axonal growth of neurons in vitro. Exp Neurol. 2012;233:783–90.
Finelli MJ, Wong JK, Zou H. Epigenetic regulation of sensory axon regeneration after spinal cord injury. J Neurosci. 2013;33:19664–76.
Kaya-Okur HS, Wu SJ, Codomo CA, Pledger ES, Bryson TD, Henikoff JG, et al. CUT&Tag for efficient epigenomic profiling of small samples and single cells. Nat Commun. 2019;10:1930.
Skene PJ, Henikoff S. An efficient targeted nuclease strategy for high-resolution mapping of DNA binding sites. Elife. 2017;6:e21856.
Balsalobre A, Drouin J. Pioneer factors as master regulators of the epigenome and cell fate. Nat Rev Mol Cell Biol. 2022;23:449–64.
Wapinski OL, Vierbuchen T, Qu K, Lee QY, Chanda S, Fuentes DR, et al. Hierarchical mechanisms for direct reprogramming of fibroblasts to neurons. Cell. 2013;155:621–35.
Su Y, Shin J, Zhong C, Wang S, Roychowdhury P, Lim J, et al. Neuronal activity modifies the chromatin accessibility landscape in the adult brain. Nat Neurosci. 2017;20:476–83.
Barbon A, Magri C. RNA editing and modifications in mood disorders. Genes. 2020;11:872.
Widagdo J, Anggono V. The m6A-epitranscriptomic signature in neurobiology: from neurodevelopment to brain plasticity. J Neurochem. 2018;147:137–52.
Abe N, Borson SH, Gambello MJ, Wang F, Cavalli V. Mammalian target of rapamycin (mTOR) activation increases axonal growth capacity of injured peripheral nerves. J Biol Chem. 2010;285:28034–43.
Liu K, Lu Y, Lee JK, Samara R, Willenberg R, Sears-Kraxberger I, et al. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat Neurosci. 2010;13:1075–81.
Barbieri I, Kouzarides T. Role of RNA modifications in cancer. Nat Rev Cancer. 2020;20:303–22.
Roundtree IA, Evans ME, Pan T, He C. Dynamic RNA modifications in gene expression regulation. Cell. 2017;169:1187–1200.
Eyler DE, Franco MK, Batool Z, Wu MZ, Dubuke ML, Dobosz-Bartoszek M, et al. Pseudouridinylation of mRNA coding sequences alters translation. Proc Natl Acad Sci USA. 2019;116:23068–74.
Schumann U, Zhang HN, Sibbritt T, Pan A, Horvath A, Gross S, et al. Multiple links between 5-methylcytosine content of mRNA and translation. BMC Biol. 2020;18:40.
Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, et al. N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell. 2015;161:1388–99.
Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 2014;10:93–95.
Yue Y, Liu J, Cui X, Cao J, Luo G, Zhang Z, et al. VIRMA mediates preferential m(6)A mRNA methylation in 3’UTR and near stop codon and associates with alternative polyadenylation. Cell Discov. 2018;4:10.
Wen J, Lv R, Ma H, Shen H, He C, Wang J, et al. Zc3h13 regulates nuclear RNA m(6)A methylation and mouse embryonic stem cell self-renewal. Mol Cell. 2018;69:1028–38.e1026.
Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014;24:177–89.
Xu H, Dzhashiashvili Y, Shah A, Kunjamma RB, Weng YL, Elbaz B, et al. m(6)A mRNA methylation is essential for oligodendrocyte maturation and CNS myelination. Neuron. 2020;105:293–309.e295.
Yoon KJ, Ringeling FR, Vissers C, Jacob F, Pokrass M, Jimenez-Cyrus D, et al. Temporal control of mammalian cortical neurogenesis by m(6)A methylation. Cell. 2017;171:877–89.e817.
Alarcon CR, Goodarzi H, Lee H, Liu X, Tavazoie S, Tavazoie SF. HNRNPA2B1 is a mediator of m(6)A-dependent nuclear RNA processing events. Cell. 2015;162:1299–308.
Huang H, Weng H, Sun W, Qin X, Shi H, Wu H, et al. Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 2018;20:285–95.
Roundtree IA, Luo GZ, Zhang Z, Wang X, Zhou T, Cui Y, et al. YTHDC1 mediates nuclear export of N(6)-methyladenosine methylated mRNAs. Elife. 2017;6:e31311.
Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014;505:117–20.
Zhou KI, Shi H, Lyu R, Wylder AC, Matuszek Z, Pan JN, et al. Regulation of co-transcriptional pre-mRNA Splicing by m(6)A through the low-complexity protein hnRNPG. Mol Cell. 2019;76:70–81.e79.
Weng YL, Wang X, An R, Cassin J, Vissers C, Liu Y, et al. Epitranscriptomic m(6)A regulation of axon regeneration in the adult mammalian nervous system. Neuron. 2018;97:313–25.e316.
Flamand MN, Meyer KD. m6A and YTHDF proteins contribute to the localization of select neuronal mRNAs. Nucleic Acids Res. 2022;50:4464–83.
Yu J, Chen M, Huang H, Zhu J, Song H, Zhu J, et al. Dynamic m6A modification regulates local translation of mRNA in axons. Nucleic Acids Res. 2018;46:1412–23.
Terenzio M, Koley S, Samra N, Rishal I, Zhao Q, Sahoo PK, et al. Locally translated mTOR controls axonal local translation in nerve injury. Science. 2018;359:1416–21.
Villa E, Sahu U, O’Hara BP, Ali ES, Helmin KA, Asara JM, et al. mTORC1 stimulates cell growth through SAM synthesis and m(6)A mRNA-dependent control of protein synthesis. Mol Cell. 2021;81:2076.e2079.
Sun HL, Zhu AC, Gao Y, Terajima H, Fei Q, Liu S, et al. Stabilization of ERK-phosphorylated METTL3 by USP5 increases m(6)A methylation. Mol Cell. 2020;80:633–47.e637.
Bertero A, Brown S, Madrigal P, Osnato A, Ortmann D, Yiangou L, et al. The SMAD2/3 interactome reveals that TGFbeta controls m(6)A mRNA methylation in pluripotency. Nature. 2018;555:256–9.
Du Y, Hou G, Zhang H, Dou J, He J, Guo Y, et al. SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function. Nucleic Acids Res. 2018;46:5195–208.
Pinto R, Vagbo CB, Jakobsson ME, Kim Y, Baltissen MP, O’Donohue MF, et al. The human methyltransferase ZCCHC4 catalyses N6-methyladenosine modification of 28S ribosomal RNA. Nucleic Acids Res. 2020;48:830–46.
Blanco S, Dietmann S, Flores JV, Hussain S, Kutter C, Humphreys P, et al. Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders. EMBO J. 2014;33:2020–39.
Liu F, Clark W, Luo G, Wang X, Fu Y, Wei J, et al. ALKBH1-mediated tRNA demethylation regulates translation. Cell. 2016;167:816–28.e816.
Tuorto F, Liebers R, Musch T, Schaefer M, Hofmann S, Kellner S, et al. RNA cytosine methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis. Nat Struct Mol Biol. 2012;19:900–5.
Levi O, Arava YS. Pseudouridine-mediated translation control of mRNA by methionine aminoacyl tRNA synthetase. Nucleic Acids Res. 2021;49:432–43.
Zhang F, Yoon K, Zhang DY, Kim NS, Ming GL, Song H. Epitranscriptomic regulation of cortical neurogenesis via Mettl8-dependent mitochondrial tRNA m(3)C modification. Cell Stem Cell. 2023;30:300–11.e311.
Ontiveros RJ, Shen H, Stoute J, Yanas A, Cui Y, Zhang Y, et al. Coordination of mRNA and tRNA methylations by TRMT10A. Proc Natl Acad Sci USA. 2020;117:7782–91.
Greenhalgh AD, David S, Bennett FC. Immune cell regulation of glia during CNS injury and disease. Nat Rev Neurosci. 2020;21:139–52.
Jakel S, Dimou L. Glial cells and their function in the adult brain: a journey through the history of their ablation. Front Cell Neurosci. 2017;11:24.
Reed CB, Feltri ML, Wilson ER. Peripheral glia diversity. J Anat. 2022;24:1219–34.
Li C, Wu Z, Zhou L, Shao J, Hu X, Xu W, et al. Temporal and spatial cellular and molecular pathological alterations with single-cell resolution in the adult spinal cord after injury. Signal Transduct Target Ther. 2022;7:65.
Faraco G, Pittelli M, Cavone L, Fossati S, Porcu M, Mascagni P, et al. Histone deacetylase (HDAC) inhibitors reduce the glial inflammatory response in vitro and in vivo. Neurobiol Dis. 2009;36:269–79.
Suh HS, Choi S, Khattar P, Choi N, Lee SC. Histone deacetylase inhibitors suppress the expression of inflammatory and innate immune response genes in human microglia and astrocytes. J Neuroimmune Pharmacol. 2010;5:521–32.
Popovich PG, Jones TB. Manipulating neuroinflammatory reactions in the injured spinal cord: back to basics. Trends Pharmacol Sci. 2003;24:13–17.
Zhou X, Wahane S, Friedl MS, Kluge M, Friedel CC, Avrampou K, et al. Microglia and macrophages promote corralling, wound compaction and recovery after spinal cord injury via Plexin-B2. Nat Neurosci. 2020;23:337–50.
Li Y, He X, Kawaguchi R, Zhang Y, Wang Q, Monavarfeshani A, et al. Microglia-organized scar-free spinal cord repair in neonatal mice. Nature. 2020;587:613–8.
Ayata P, Badimon A, Strasburger HJ, Duff MK, Montgomery SE, Loh YE, et al. Epigenetic regulation of brain region-specific microglia clearance activity. Nat Neurosci. 2018;21:1049–60.
Duncan GJ, Manesh SB, Hilton BJ, Assinck P, Plemel JR, Tetzlaff W. The fate and function of oligodendrocyte progenitor cells after traumatic spinal cord injury. Glia. 2020;68:227–45.
Gregath A, Lu QR. Epigenetic modifications-insight into oligodendrocyte lineage progression, regeneration, and disease. FEBS Lett. 2018;592:1063–78.
Wahane S, Zhou X, Zhou X, Guo L, Friedl MS, Kluge M, et al. Diversified transcriptional responses of myeloid and glial cells in spinal cord injury shaped by HDAC3 activity. Sci Adv. 2021;7:eabd8811.
Kuboyama T, Wahane S, Huang Y, Zhou X, Wong JK, Koemeter-Cox A, et al. HDAC3 inhibition ameliorates spinal cord injury by immunomodulation. Sci Rep. 2017;7:8641.
Bailey ZS, Grinter MB, VandeVord PJ. Astrocyte reactivity following blast exposure involves aberrant histone acetylation. Front Mol Neurosci. 2016;9:64.
Zhang ZY, Zhang Z, Fauser U, Schluesener HJ. Global hypomethylation defines a sub-population of reactive microglia/macrophages in experimental traumatic brain injury. Neurosci Lett. 2007;429:1–6.
Gasparoni G, Bultmann S, Lutsik P, Kraus TFJ, Sordon S, Vlcek J, et al. DNA methylation analysis on purified neurons and glia dissects age and Alzheimer’s disease-specific changes in the human cortex. Epigenetics Chromatin. 2018;11:41.
Hung HA, Sun G, Keles S, Svaren J. Dynamic regulation of Schwann cell enhancers after peripheral nerve injury. J Biol Chem. 2015;290:6937–50.
Zeisel A, Munoz-Manchado AB, Codeluppi S, Lonnerberg P, La Manno G, Jureus A, et al. Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science. 2015;347:1138–42.
Rosenberg AB, Roco CM, Muscat RA, Kuchina A, Sample P, Yao Z, et al. Single-cell profiling of the developing mouse brain and spinal cord with split-pool barcoding. Science. 2018;360:176–82.
Shin J, Berg DA, Zhu Y, Shin JY, Song J, Bonaguidi MA, et al. Single-cell RNA-Seq with waterfall reveals molecular cascades underlying adult neurogenesis. Cell Stem Cell. 2015;17:360–72.
Lake BB, Ai R, Kaeser GE, Salathia NS, Yung YC, Liu R, et al. Neuronal subtypes and diversity revealed by single-nucleus RNA sequencing of the human brain. Science. 2016;352:1586–90.
Zhu C, Yu M, Huang H, Juric I, Abnousi A, Hu R, et al. An ultra high-throughput method for single-cell joint analysis of open chromatin and transcriptome. Nat Struct Mol Biol. 2019;26:1063–70.
Zhu C, Zhang Y, Li YE, Lucero J, Behrens MM, Ren B. Joint profiling of histone modifications and transcriptome in single cells from mouse brain. Nat Methods. 2021;18:283–92.
Trapnell C, Cacchiarelli D, Grimsby J, Pokharel P, Li S, Morse M, et al. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat Biotechnol. 2014;32:381–6.
Stuart T, Satija R. Integrative single-cell analysis. Nat Rev Genet. 2019;20:257–72.
Butler A, Hoffman P, Smibert P, Papalexi E, Satija R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol. 2018;36:411–20.
Tuszynski Mark H, Steward O. Concepts and methods for the study of axonal regeneration in the CNS. Neuron. 2012;74:777–91.
Cooke P, Janowitz H, Dougherty SE. Neuronal redevelopment and the regeneration of neuromodulatory axons in the adult mammalian central nervous system. Front Cell Neurosci. 2022;16:872501.
Tian F, Cheng Y, Zhou S, Wang Q, Monavarfeshani A, Gao K, et al. Core transcription programs controlling injury-induced neurodegeneration of retinal ganglion cells. Neuron. 2022;110:2607–24.e2608.
Jacobi A, Tran NM, Yan W, Benhar I, Tian F, Schaffer R, et al. Overlapping transcriptional programs promote survival and axonal regeneration of injured retinal ganglion cells. Neuron. 2022;110:2625–45.e2627.
Li L, Fang F, Feng X, Zhuang P, Huang H, Liu P, et al. Single-cell transcriptome analysis of regenerating RGCs reveals potent glaucoma neural repair genes. Neuron. 2022;110:2646–63.e2646.
Hammond TR, Dufort C, Dissing-Olesen L, Giera S, Young A, Wysoker A, et al. Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes. Immunity. 2019;50:253–71.e256.
Milich LM, Choi JS, Ryan C, Cerqueira SR, Benavides S, Yahn SL, et al. Single-cell analysis of the cellular heterogeneity and interactions in the injured mouse spinal cord. J Exp Med. 2021;218:e20210040.
Hasel P, Rose IVL, Sadick JS, Kim RD, Liddelow SA. Neuroinflammatory astrocyte subtypes in the mouse brain. Nat Neurosci. 2021;24:1475–87.
Meyer KD. DART-seq: an antibody-free method for global m(6)A detection. Nat Methods. 2019;16:1275–80.
Tegowski M, Flamand MN, Meyer KD. scDART-seq reveals distinct m(6)A signatures and mRNA methylation heterogeneity in single cells. Mol Cell. 2022;82:868–78.e810.
Kaplan GB, Leite-Morris KA, Wang L, Rumbika KK, Heinrichs SC, Zeng X, et al. Pathophysiological bases of comorbidity: traumatic brain injury and post-traumatic stress disorder. J Neurotrauma. 2018;35:210–25.
The research in the authors’ laboratories were supported by grants from the National Institutes of Health (R35NS116843 to HS, R35NS097370 to G-lM, R01ES031511 to Y-LW), Houston Methodist Neurospark (to Y-LW), and Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to G-lM). Figures were created with BioRender.com.
The authors declare no competing interests.
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Cheng, Y., Song, H., Ming, Gl. et al. Epigenetic and epitranscriptomic regulation of axon regeneration. Mol Psychiatry 28, 1440–1450 (2023). https://doi.org/10.1038/s41380-023-02028-9