m6A修饰在脊髓损伤恢复中的研究进展

doi:10.3969/j.issn.1006-5725.2023.20.021

Abstract

Abstract:

Spinal cord injury （SCI） is a serious disease of the central nervous system （CNS）， which often leads to motor dysfunction and is associated with a variety of serious complications， seriously affecting the quality of life of patients. N6-methyladenosine （m6A） is a methylation modification that occurs at the N6 site of adenosine， also known as the m6A methylation modification， which is of great interest because of its great potential for diagnosis and treatment of neurological diseases. m6A modifications are catalyzed by methyltransferases， removed by demethylases， recognized by methyl-recognition proteins， and its associated regulatory proteins can affect the development of SCI and its secondary damage through various pathways. Up to now， the mechanism of m6A modification in SCI has not been fully elucidated. In this paper， we review the basic functions of m6A modification and its role and mechanism in SCI.

Key words: N6- methyladenosine, spinal cord injury, RNA modification

CLC Number:

R744

Dongxu ZHANG,Xinhua ZHAO,Huanying JIANG,Lixin ZHOU,Zhongren SUN,Hongna. YIN. Research progress of m6A modification in spinal cord injury recovery[J]. The Journal of Practical Medicine, 2023, 39(20): 2676-2682.

Figures/Tables 3

Fig. 1

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Tab. 1

References 53

1	GILBERT E A B ， LAKSHMAN N ， LAU K S K ， et al . Regulating Endogenous Neural Stem Cell Act-ivation to Promote Spinal Cord Injury Repair ［J］. Cells，2022， 11（5）：846.
2	BIE F ， WANG K ， XU T ， et al . The potential roles of circular RNAs as modulators in traumatic spinal cord injury ［J］. Biomed Pharmacother， 2021，141：111826.
3	BONIZZATO M ， JAMES N D ， PIDPRUZHNYKOVA G ， et al . Multi-pronged neuromodulation intervention engages the residual motor circuitry to facilitate walking in a rat model of spinal cord injury ［J］. Nat Commun， 2021， 12（1）：1925.
4	ZHANG T ， ZHANG S W ， ZHANG S Y ， et al . m6A-express： uncovering complex and condition-specific m6A regulation of gene expression ［J］. Nucleic Acids Res， 2021， 49（20）：e116.
5	郭岩松，李思柔，李琳，等 . m6A修饰在胶质瘤中的研究进展［J］. 实用医学杂志，2023，39（13）：1724-1728..
6	LIU D ， FAN B ， LI J ， et al . N6-methyladenosine modification： A potential regulatory mechanism in spinal cord injury ［J］. Front Cell Neurosci， 2022， 16：989637.
7	LI L ， XU N ， LIU J ， et al . m6A Methylation in Cardiovascular Diseases： From Mechanisms to Therapeutic Potential ［J］. Front Genet， 2022，13：908976.
8	TIAN M ， MAO L ， ZHANG L . Crosstalk among N6-methyladenosine modification and RNAs in central nervous system injuries ［J］. Front Cell Neurosci，2022， 16：1013450.
9	ZACCARA S ， RIES R J ， JAFFREY S R . Reading， writing and erasing mRNA methylation ［J］. Nat Rev Mol Cell Biol， 2019， 20（10）：608-624.
10	ZHAO W ， QI X ， LIU L ， et al . Epigenetic Regulation of m6A Modifications in Human Cancer ［J］. Mol Ther Nucleic Acids， 2020， 19：405-412.
11	XU Z ， PENG B ， CAI Y ， et al . N6-methyladenosine RNA modification in cancer therapeutic resistance： Current status and perspectives ［J］. Biochem Pharmacol， 2020， 182：114258.
12	ZENG C ， HUANG W ， LI Y ， et al . Roles of METTL3 in cancer： mechanisms and therapeutic targeting ［J］. J Hematol Oncol， 2020， 13（1）：117.
13	OERUM S ， MEYNIER V ， CATALA M ， et al . A comprehensive review of m6A/m6Am RNA methyltransferase structures ［J］. Nucleic Acids Res，2021，49（13）：7239-7255.
14	YANG Y ， HUANG G ， JIANG X ， et al . Loss of Wtap results in cerebellar ataxia and degeneration of Purkinje cells ［J］. J Genet Genomics， 2022，49（9）：847-858.
15	AZZAM S K ， ALSAFAR H ， SAJINI A A . FTO m6A Demethylase in Obesity and Cancer： Implications and Underlying Molecular Mechanisms ［J］. Int J Mol Sci，2022， 23（7）：3800.
16	CHOKKALLA A K ， JEONG S ， MEHTA S L ， et al . Cerebroprotective Role of N6-Met-hyladenosineDemethylase FTO （Fat Mass and Obesity-Associated Protein） After Experimental Stroke ［J］.Stroke， 2023， 54（1）：245-254.
17	LIU Y ， YUAN Q ， XIE L . The AlkB Family of Fe （II）/Alpha-Ketoglutarate-Dependent Dioxygenases Modulates Embryogenesis through Epigenetic Regulation ［J］. Curr Stem Cell Res Ther， 2018， 13（2）：136-143.
18	COVELO MOLARES H ， OBRDLIK A ， POŠTULKOVÁ I ， et al . The comprehensive interactomes of human adenosine RNA methyltransferases and demethylases reveal distinct functional and regulatory features ［J］. Nucleic Acids Res， 2021， 49（19）：10895-10910.
19	HUANG J ， SHAO Y ， GU W . Function and clinical significance of N6-methyladenosine in digestive system tumours ［J］. Exp Hematol Oncol，2021， 10（1）：40.
20	HUANG H ， WENG H ， SUN W ， et al . Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation ［J］. Nat Cell Biol， 2018， 20（3）：285-295.
21	ORR M B ， GENSEL J C . Spinal Cord Injury Scarring and Inflammation： Therapies Targeting Glial and Inflammatory Responses ［J］. Neurotherapeutics， 2018， 15（3）：541-553.
22	ZHOU X ， WAHANE S ， FRIEDL M S ， et al . Microglia and macrophages promote corralling， wound compaction and recovery after spinal cord injury via Plexin-B2 ［J］. Nat Neuro Sci， 2020， 23（3）：337-350.
23	LIU W ， RONG Y ， WANG J ， et al . Exosome-shuttled miR-216a-5p from hypoxic prec-onditioned mesenchymal stem cells repair traumatic spinal cord injury by shifting microglial M1/M2 polarization ［J］. J Neuroinflammation， 2020， 17（1）：47.
24	CHEN F ， HU M ， SHEN Y ， et al . Isorhamnetin promotes functional recovery in rats with spinal cord injury by abating oxidative stress and modulating M2 macrophages/microglia polarization ［J］. Eur J Pharmacol， 2021， 895：173878.
25	ZHOU H ， XU Z ， LIAO X ， et al . Low Expression of YTH Domain-Containing 1 Promotes Microglial M1 Polarization by Reducing the Stability of Sirtuin 1 mRNA ［J］. Front Cell Neuro Sci， 2021， 15：774305.
26	WEN L ， SUN W ， XIA D ， et al . The m6A methyltransferase METTL3 promotes LPS induced microglia inflammation through TRAF6/NF-κB pathway ［J］. Neuro Report， 2022， 33（6）：243-251.
27	DING L ， WU H ， WANG Y ， et al . m6A Reader Igf2bp1 Regulates the Inflammatory Responses of Microglia by Stabilizing Gbp11 and Cp mRNAs ［J］. Front Immunol， 2022， 13：872252.
28	LI Q ， WEN S ， YE W ， et al . The potential roles of m6A modification in regulating the inflammatory response in microglia ［J］. J Neuroinflammation， 2021， 18（1）：149.
29	WU J ， WANG X ， LI X . N6-methyladenosine methylation regulator FTO promotes oxidative stress and induces cell apoptosis in ovarian cancer ［J］. Epigenomics， 2022， 14（23）：1509-1522.
30	HUANG W ， LIN M ， YANG C ， et al . Rat Bone Mesenchymal Stem Cell-Derived Exosomes Loaded with miR-494 Promoting Neurofilament Regeneration and Behavioral Function Recovery after Spinal Cord Injury ［J］. Oxid Med Cell Longev， 2021， 2021：1634917.
31	LI X ， AN P ， HAN F ， et al . Silencing of YTHDF1 Attenuates Cerebral Stroke by Inducing PTEN Degradation and Activating the PTEN/AKT/mTOR Pathway ［J］. Mol Bio technol， 2023，65（5）：822-832.
32	WANG C X ， CUI G S ， LIU X ， et al . METTL3-mediated m6A modification is required for cerebellar development ［J］. PLoS Biol， 2018， 16（6）：e2004880.
33	MING Y ， DENG Z ， TIAN X ， et al . m6A Methyltransferase METTL3 Reduces Hippocampal Neuron Apoptosis in a Mouse Model of Autism Through the MALAT1/SFRP2/Wnt/β-catenin Axis ［J］. Psychiatry Investig， 2022， 19（10）：771-787.
34	WANG H ， YUAN J ， DANG X ， et al . Mettl14-mediated m6A modification modulates neuro-n apoptosis during the repair of spinal cord injury by regulating the transformation f-rompri-mir-375 to miR-375 ［J］. Cell Biosci， 2021， 11（1）：52.
35	YANG J ， XIONG L L ， WANG Y C ， et al . Oligodendrocyte precursor cell transplantation promotes functional recovery following contusive spinal cord injury in rats and is associate-d with altered microRNA expression ［J］. Mol Med Rep， 2018， 17（1）：771-782.
36	WIRAKIAT W ， PROMMAHOM A ， DHARMASAROJA P . Inhibition of the antioxidant enzyme PR-DX1 activity promotes MPP+-induced death in differentiated SH-SY5Y cells and may i-mpair its colocalization with eEF1A2 ［J］. Life Sci， 2020， 258：118227.
37	GAO G ， DUAN Y ， CHANG F ， et al . METTL14 promotes apoptosis of spinal cord neurons by inducing EEF1A2 m6A methylation in spinal cord injury ［J］. Cell Death Discov， 2022， 8（1）：15.
38	VISMARA I ， PAPA S ， VENERUSO V ， et al . Selective Modulation of A1 Astrocytes by Drug-Loaded Nano-Structured Gel in Spinal Cord Injury ［J］. ACS Nano， 2020， 14（1）：360-371.
39	ZHOU Z L ， XIE H ， TIAN X B ， et al . Microglial depletion impairs glial scar formation and aggravates inflammation partly by inhibiting STAT3 phosphorylation in astrocytes after spinal cord injury ［J］. Neural Regen Res， 2023， 18（6）：1325-1331.
40	韦入菲，曾高峰 . 减少脊髓损伤后胶质瘢痕形成方法的研究进展［J］. 实用医学杂志，2020， 36（20）：2876-2880.
41	TENG Y ， LIU Z ， CHEN X ， et al . Conditional deficiency of m6A methyltransferase Mettl14 in substantia nigra alters dopaminergic neuron function ［J］. J Cell Mol Med， 2021， 25（17）：8567-8572.
42	HUANG R ， ZHANG Y ， BAI Y ， et al . N6-Methyladenosine Modification of Fatty Acid Amide-Hydrolase Messenger RNA in Circular RNA STAG1-Regulated Astrocyte Dysfunction and Depressive-like Behaviors ［J］. Biol Psychiatry， 2020， 88（5）：392-404.
43	GE X ， YE W ， ZHU Y ， et al . USP1/UAF1-Stabilized METTL3 Promotes Reactive Astrogliosis and Improves Functional Recovery after Spinal Cord Injury through m6A Modification of YAP1 mRNA ［J］. J Neuro Sci， 2023， 43（9）：1456-1474.
44	XING L ， CAI Y ， YANG T ， et al . Epi transcriptomic m6A regulation following spinal cord in-jury ［J］. J Neuro Sci Res， 2021， 99（3）：843-857.
45	VARADARAJAN S G ， HUNYARA J L ， HAMILTON N R ， et al . Central nervous system regeneration ［J］. Cell， 2022， 185（1）：77-94.
46	HOU Y ， LIU X ， GUO Y ， et al . Strategies for Effective Neural Circuit Reconstruction After Spinal Cord Injury： Use of Stem Cells and Biomaterials ［J］. World Neuro Surg， 2022， 161：82-89.
47	HUANG L ， FU C ， XIONG F ， et al . Stem Cell Therapy for Spinal Cord Injury ［J］. Cell Transplant， 2021， 30：963689721989266.
48	YU J ， CHEN M ， HUANG H ， et al . Dynamic m6A modification regulates local translation of mRNA in axons ［J］. Nucleic Acids Res， 2018， 46（3）：1412-1423.
49	YU J ， SHE Y ， YANG L ， et al . The m6 A Readers YTHDF1 and YTHDF2 Synergistically Control Cerebellar Parallel Fiber Growth by Regulating Local Translation of the Key Wnt5a Signaling Components in Axons ［J］. Adv Sci （Weinh）， 2021， 8（22）：e2101329.
50	ZHUANG M ， LI X ， ZHU J ， et al . The m6A reader YTHDF1 regulates axon guidance thro-ugh translational control of Robo3.1 expression ［J］. Nucleic Acids Res， 2019， 47（9）：4765-4777.
51	YOUNOSSI-HARTENSTEIN A ， JONES M ， HARTENSTEIN V . Embryonic development of the nervous system of the temnocephalid flatworm Craspedella pedum ［J］. J Comp Neurol， 2001， 434（1）：56-68.
52	LI C ， ZHAO J ， QIN T ， et al . Comprehensive analysis of m6A methylation modification in chronic spinal cord injury in mice ［J］. J Orthop Res， 2023，41（6）：1320-1334.
53	LEI C ， WANG Q . The Progression of N6-methyladenosine Study and Its Role in Neuro-psychiatric Disorders ［J］. Int J Mol Sci， 2022， 23（11）：5922.

SCI 病理表型	m6A 相关蛋白	功能	目标基因	机制	参考文献
炎症反应	METTL3	甲基转移酶	TRAF6	SCI后敲低METTL3抑制其以m6A依赖的方式激活TRAF6?NF?κB通路，抑制小胶质细胞向M1型转化，降低炎性反应	［26］
炎症反应	IGF2BP1	M6A结合蛋白	GBP11	SCI后IGF2BP1的敲低降低了GBP11的m6A甲基化水平及稳定性，抑制小胶质细胞的炎症反应	［27］
细胞凋亡	METTL14	甲基转移酶	Pri?miR?375	SCI后METTL14的敲除可阻止pri?miR?375向抑制细胞增殖的miR?375的转化，从而抑制细胞凋亡	［34］
细胞凋亡	METTL14	甲基转移酶	EEF1A2	SCI后敲低METTL14，可使 EEF1A2表达上调，在抑制了损伤部位细胞凋亡的同时还可减少炎症细胞因子的产生及脊髓中的神经元变性	［36］
胶质瘢痕	METTL3	甲基转移酶	GFAP	敲除METTL3的SCI大鼠GFAP表达显著降低，减少了损伤部位反应性星形胶质细胞的数量，抑制了胶质瘢痕形成，但这也导致了损伤部位炎症广泛扩散，轴突再生受限，大量神经元死亡	［43］
胶质瘢痕	METTL14	甲基转移酶	GFAP	SCI后METTL3在星形胶质细胞中的表达显著增加，这可能对星形胶质细胞的形态和功能产生了影响，但对于METTL3的变化对胶质瘢痕的影响还需进一步实验阐明	［44］
轴突再生	METTL14	甲基转移酶	AcTub	SCI后对METTL14进行敲除，轴突生长特异性标记物AcTub的表达显著上调，这表明METTL14对SCI后轴突生长具有调控作用	［34］、［51］

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Research progress of m6A modification in spinal cord injury recovery

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