Skip to main content

Advertisement

SpringerLink
Log in

HIF-1α-induced upregulation of m6A reader IGF2BP1 facilitates peripheral nerve injury recovery by enhancing SLC7A11 mRNA stabilization

  • Published:
In Vitro Cellular & Developmental Biology - Animal Aims and scope Submit manuscript

Abstract

The recovery of peripheral nerve injury (PNI) is not ideal in clinic. Our previous study revealed that hypoxia treatment promoted PNI repair by inhibiting ferroptosis. The aim of this study was to investigate the underlying molecular mechanism of HIF-1α in hypoxia-PNI recovery. M6A dot blot was used to determine the total level of m6A modification. Besides, HIF-1α small interfering RNA (siRNA) or IGF2BP1 overexpression vector was transfected into dorsal root ganglion (DRG) neurons to alter the expression of HIF-1α and IGF2BP1. Subsequently, MeRIP-PCR analysis was applied to validate the m6A methylation level of SLC7A11. We demonstrated the hypoxia stimulated HIF-1α-dependent expression of IGF2BP1 and promoted the overall m6A methylation levels of DRG neurons. Overexpression of HIF-1α increased the expressions of neurotrophic factors including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial-derived neurotrophic factor (GDNF), which could be effectively reversed by siRNA knockdown of IGF2BP1. Moreover, upregulation of HIF-1α contributed to the m6A methylation level and mRNA stabilization of SLC7A11. This study revealed that the HIF-1α/IGF2BP1/SLC7A11 regulatory axis facilitated the recovery of injured DRG neurons. Our findings suggest a novel insight for the m6A methylation modification in PNI recovery.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1.
Figure 2.
Figure 3.
Figure 4.
Figure 5.

Similar content being viewed by others

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  • An S, Shi J, Li Z, Feng M, Cao G (2022) The effects of acrylamide-mediated dorsal root ganglion neurons injury on ferroptosis. Hum Exp Toxico 41:9603271221129786

    Article  CAS  Google Scholar 

  • An S, Zhou M, Li Z, Feng M, Cao G, Lu S, Liu L (2018) Administration of CoCl2 improves functional recovery in a rat model of sciatic nerve transection injury. Int J Med Sci 15:1423–1432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bergmeister KD, Große-Hartlage L, Daeschler SC, Rhodius P, Böcker A, Beyersdorff M, Kern AO, Kneser U, Harhaus L (2020) Acute and long-term costs of 268 peripheral nerve injuries in the upper extremity. PLoS One 15:e0229530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berulava T, Buchholz E, Elerdashvili V, Pena T, Islam MR, Lbik D, Mohamed BA, Renner A, Von Lewinski D, Sacherer M, Bohnsack KE, Bohnsack MT, Jain G, Capece V, Cleve N, Burkhardt S, Hasenfuss G, Fischer A, Toischer K (2020) Changes in m6A RNA methylation contribute to heart failure progression by modulating translation. Eur J Heart Fail 22:54–66

    Article  CAS  PubMed  Google Scholar 

  • Chen X, Xiao J-W, Cao P, Zhang Y, Cai W-J, Song J-Y, Gao W-M, Li B (2021) Brain-derived neurotrophic factor protects against acrylamide-induced neuronal and synaptic injury via the TrkB-MAPK-Erk1/2 pathway. Neural Regen Res 16:150–157

    Article  CAS  PubMed  Google Scholar 

  • Cho Y, Shin Jung E, Ewan Eric E, Oh Young M, Pita-Thomas W, Cavalli V (2015) Activating injury-responsive genes with hypoxia enhances axon regeneration through neuronal HIF-1α. Neuron 88:720–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Faroni A, Mobasseri SA, Kingham PJ, Reid AJ (2015) Peripheral nerve regeneration: experimental strategies and future perspectives. Adv Drug Deliv Rev 82–83:160–167

    Article  PubMed  Google Scholar 

  • Grinsell D, Keating CP (2014) Peripheral nerve reconstruction after injury: a review of clinical and experimental therapies. BioMed Res Int 2014:698256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han J, Wang J-Z, Yang X, Yu H, Zhou R, Lu H-C, Yuan W-B, Lu J-C, Zhou Z-J, Lu Q, Wei J-F, Yang H (2019) METTL3 promote tumor proliferation of bladder cancer by accelerating pri-miR221/222 maturation in m6A-dependent manner. Mol Cancer 18:110

    Article  PubMed  PubMed Central  Google Scholar 

  • Han M, Liu Z, Xu Y, Liu X, Wang D, Li F, Wang Y, Bi J (2020) Abnormality of m6A mRNA methylation is involved in Alzheimer’s disease. Front Neurosci 14:98

    Article  PubMed  PubMed Central  Google Scholar 

  • He L, Li H, Wu A, Peng Y, Shu G, Yin G (2019) Functions of N6-methyladenosine and its role in cancer. Mol Cancer 18:176

    Article  PubMed  PubMed Central  Google Scholar 

  • Huang H, Weng H, Sun W, Qin X, Shi H, Wu H, Zhao BS, Mesquita A, Liu C, Yuan CL, Hu Y-C, Hüttelmaier S, Skibbe JR, Su R, Deng X, Dong L, Sun M, Li C, Nachtergaele S, Wang Y, Hu C, Ferchen K, Greis KD, Jiang X, Wei M, Qu L, Guan J-L, He C, Yang J, Chen J (2018) Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol 20:285–295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang X, Liu B, Nie Z, Duan L, Xiong Q, Jin Z, Yang C, Chen Y (2021) The role of m6A modification in the biological functions and diseases. Signal Transduct Target Ther 6:74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Keswani Sanjay C, Bosch-Marcé M, Reed N, Fischer A, Semenza Gregg L, Höke A (2011) Nitric oxide prevents axonal degeneration by inducing HIF-1–dependent expression of erythropoietin. Proc Natl Acad Sci 108:4986–4990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee Y-C, Chang Y-C, Wu C-C, Huang C-C (2018) Hypoxia-preconditioned human umbilical vein endothelial cells protect against neurovascular damage after hypoxic ischemia in neonatal brain. Mol Neurobiol 55:7743–7757

    Article  CAS  PubMed  Google Scholar 

  • Li Q, Peng F, Yan X, Chen Y, Zhou J, Wu S, Jiang W, Jin X, Liang J, Peng C, Pan X (2023) Inhibition of SLC7A11-GPX4 signal pathway is involved in aconitine-induced ferroptosis in vivo and in vitro. J Ethnopharmacol 303:116029

    Article  CAS  PubMed  Google Scholar 

  • Li J, Xie H, Ying Y, Chen H, Yan H, He L, Xu M, Xu X, Liang Z, Liu B, Wang X, Zheng X, Xie L (2020) YTHDF2 mediates the mRNA degradation of the tumor suppressors to induce AKT phosphorylation in N6-methyladenosine-dependent way in prostate cancer. Mol Cancer 19:152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li J, Yang X, Qi Z, Sang Y, Liu Y, Xu B, Liu W, Xu Z, Deng Y (2019) The role of mRNA m6A methylation in the nervous system. Cell Biosci 9:66

    Article  PubMed  PubMed Central  Google Scholar 

  • Li L, Zang L, Zhang F, Chen J, Shen H, Shu L, Liang F, Feng C, Chen D, Tao H, Xu T, Li Z, Kang Y, Wu H, Tang L, Zhang P, Jin P, Shu Q, Li X (2017) Fat mass and obesity-associated (FTO) protein regulates adult neurogenesis. Hum Mol Genet 26:2398–2411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin AMY, Dung S-W, Chen C-F, Chen W-H, Ho L-T (2003) Hypoxic preconditioning prevents cortical infarction by transient focal ischemia-reperfusion. Ann N Y Acad Sci 993:168–178

    Article  PubMed  Google Scholar 

  • Lin Y-T, Ro L-S, Wang H-L, Chen J-C (2011) Up-regulation of dorsal root ganglia BDNF and trkB receptor in inflammatory pain: an in vivo and in vitrostudy. J Neuroinflammation 8:126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin Z, Niu Y, Wan A, Chen D, Liang H, Chen X, Sun L, Zhan S, Chen L, Cheng C, Zhang X, Bu X, He W, Wan G (2020) RNA m(6) A methylation regulates sorafenib resistance in liver cancer through FOXO3-mediated autophagy. EMBO J 39:e103181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luo Z, Wu F, Xue E, Huang L, Yan P, Pan X, Zhou Y (2019) Hypoxia preconditioning promotes bone marrow mesenchymal stem cells survival by inducing HIF-1α in injured neuronal cells derived exosomes culture system. Cell Death Dis 10:134

    Article  PubMed  PubMed Central  Google Scholar 

  • Ma S, Chen C, Ji X, Liu J, Zhou Q, Wang G, Yuan W, Kan Q, Sun Z (2019) The interplay between m6A RNA methylation and noncoding RNA in cancer. J Hematol Oncol 12:121

    Article  PubMed  PubMed Central  Google Scholar 

  • Mancarella C, Scotlandi K (2020) IGF2BP3 from physiology to cancer: novel discoveries, unsolved issues, and future perspectives. Front Cell Dev Biol 7:363

    Article  PubMed  PubMed Central  Google Scholar 

  • Modrak M, MaH T, Gurgenashvili K, Noble M, Elfar JC (2020) Peripheral nerve injury and myelination: potential therapeutic strategies. J Neurosci Res 98:780–795

    Article  CAS  PubMed  Google Scholar 

  • Nishino J, Kim S, Zhu Y, Zhu H,Morrison SJ (2013) A network of heterochronic genes including Imp1 regulates temporal changes in stem cell properties. eLife 2:e00924

  • Qin Y, Li L, Luo E, Hou J, Yan G, Wang D, Qiao Y, Tang C (2020) Role of m6A RNA methylation in cardiovascular disease (Review). Int J Mol Med 46:1958–1972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robin JR, Jae-Jun B, Anum W, Norihiko T, Jung-Whan K (2014) Regulation of wound healing and fibrosis by hypoxia and hypoxia-inducible factor-1. Mol Cells 37:637–643

    Article  Google Scholar 

  • Rybnikova E, Glushchenko T, Tyulkova E, Baranova K, Samoilov M (2009) Mild hypobaric hypoxia preconditioning up-regulates expression of transcription factors c-Fos and NGFI-A in rat neocortex and hippocampus. Neurosci Res 65:360–366

    Article  CAS  PubMed  Google Scholar 

  • Semenza GL (2012) Hypoxia-inducible factors in physiology and medicine. Cell 148:399–408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stowe AM, Altay T, Freie AB, Gidday JM (2011) Repetitive hypoxia extends endogenous neurovascular protection for stroke. Ann Neurol 69:975–985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsai Y-W, Yang Y-R, Wang PS, Wang R-Y (2011) Intermittent hypoxia after transient focal ischemia induces hippocampal neurogenesis and c-Fos expression and reverses spatial memory deficits in rats. PLoS ONE 6:e24001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang W, Shi F, Cui J, Pang S, Zheng G, Zhang Y (2022) MiR-378a-3p/ SLC7A11 regulate ferroptosis in nerve injury induced by lead exposure. Ecotoxicol Environ Saf 239:113639

    Article  CAS  PubMed  Google Scholar 

  • Wilkinson E, Cui Y-H, He Y-Y (2022) Roles of RNA modifications in diverse cellular functions. Front Cell Dev Biol 10:828683

    Article  PubMed  PubMed Central  Google Scholar 

  • Xu H, Dzhashiashvili Y, Shah A, Kunjamma RB, Weng Y-L, Elbaz B, Fei Q, Jones JS, Li YI, Zhuang X, Ming G-L, He C, Popko B (2020) m(6)A mRNA methylation is essential for oligodendrocyte maturation and CNS myelination. Neuron 105:293-309.e5

    Article  CAS  PubMed  Google Scholar 

  • Yaniv K, Fainsod A, Kalcheim C, Yisraeli JK (2003) The RNA-binding protein Vg1 RBP is required for cell migration during early neural development. Development 130:5649–5661

    Article  CAS  PubMed  Google Scholar 

  • Yao B, Christian KM, He C, Jin P, Ming G-L, Song H (2016) Epigenetic mechanisms in neurogenesis. Nat Rev Neurosci 17:537–549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ying Y, Ma X, Fang J, Chen S, Wang W, Li J, Xie H, Wu J, Xie B, Liu B, Wang X, Zheng X, Xie L (2021) EGR2-mediated regulation of m6A reader IGF2BP proteins drive RCC tumorigenesis and metastasis via enhancing S1PR3 mRNA stabilization. Cell Death Dis 12:750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu J, Chen M, Huang H, Zhu J, Song H, Zhu J, Park J, Ji S-J (2018) Dynamic m6A modification regulates local translation of mRNA in axons. Nucleic Acids Res 46:1412–1423

    Article  CAS  PubMed  Google Scholar 

  • Zhao Y, Hu J, Sun X, Yang K, Yang L, Kong L, Zhang B, Li F, Li C, Shi B, Hu K, Sun A, Ge J (2021) Loss of m6A demethylase ALKBH5 promotes post-ischemic angiogenesis via post-transcriptional stabilization of WNT5A. Clin Transl Med 11:e402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou H, Wang B, Sun H, Xu X, Wang Y (2018) Epigenetic regulations in neural stem cells and neurological diseases. Stem Cells Int 2018:6087143

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The research was supported by the Capital Health Research and Development of Special (2020–4-2018).

Author information

Author notes

  1. Shuai An and Jingfei Shi contributed equally to this work.

Authors and Affiliations

  1. Department of Orthopedics, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China

    Shuai An, Jiang Huang, Zheng Li, Mingli Feng & Guanglei Cao

  2. Cerebrovascular and Neuroscience Research Institute, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, Beijing, China

    Jingfei Shi

Authors
  1. Shuai An
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jingfei Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zheng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mingli Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guanglei Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.A. conceived the experiment. S.A., J.S. J.H., and Z.L. conducted the experiment. M.F., G.C., and S.A. analyzed the results. S.A. and J.S. drafted the manuscript. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Mingli Feng or Guanglei Cao.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Supplementary information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 336 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

An, S., Shi, J., Huang, J. et al. HIF-1α-induced upregulation of m6A reader IGF2BP1 facilitates peripheral nerve injury recovery by enhancing SLC7A11 mRNA stabilization. In Vitro Cell.Dev.Biol.-Animal 59, 596–605 (2023). https://doi.org/10.1007/s11626-023-00812-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11626-023-00812-z

Keywords

Search

Navigation