Skip to main content
Log in

Expression of G9a in Auditory Cortex Is Downregulated in a Rat Model of Age-Related Hearing Loss

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

G9a is essential for dendritic plasticity and is associated with neurological disorders. The possible relationship between age-related hearing loss and G9a expression in the auditory cortex has not been fully explored. This study aimed to understand the expression patterns of G9a-mediated histone methylations in the auditory cortex during aging. Using immunofluorescence and western blotting, we demonstrated that a significant reduction in G9a expression observed in the auditory cortex of 24-month-old rats compared to 3-month-old rats, was associated with remarkable hearing threshold elevation and hair cell loss. Correspondingly, histone H3 lysine 9 (H3K9) mono- and dimethylation (marked by H3K9me1 and H3K9me2, respectively), which were regulated by G9a activity, also evidently decreased during aging. These findings, which merit further investigation, suggest a possible association between G9a-mediated histone methylations and central age-related hearing disorders.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Akiko, Takahashi, and, Yoshinori, Imai, and, Kimi, Yamakoshi, and, Shinji (2011) DNA damage signaling triggers degradation of histone methyltransferases through APC/CCdh1 in senescent cells. Mol Cell 45:123–131

  • Antignano F, Burrows K, Hughes MR, Han JM, Zaph C (2014) Methyltransferase G9A regulates T cell differentiation during murine intestinal inflammation. J Clin Invest 124(5):1945–1955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Balaram P, Hackett TA, Polley DB (2019) Synergistic transcriptional changes in AMPA and GABAA receptor genes support compensatory plasticity following unilateral hearing loss. Neuroscience 407:108–119

    Article  CAS  PubMed  Google Scholar 

  • Booth LN, Brunet A (2016) The aging epigenome. Mol Cell 62(5):728–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cha ST, Tan CT, Chang CC, Chu CY, Lee WJ, Lin BZ, Lin MT, Kuo ML (2016) G9a/RelB regulates self-renewal and function of colon-cancer-initiating cells by silencing let-7b and activating the K-RAS/β-catenin pathway. Nat Cell Biol 18(9):993–1005

    Article  CAS  PubMed  Google Scholar 

  • Cho HS, Kelly JD, Hayami S, Toyokawa G, Takawa M, Yoshimatsu M, Tsunoda T, Field HI, Neal DE, Ponder BAJ (2011) Enhanced expression of EHMT2 is involved in the proliferation of cancer cells through negative regulation of SIAH1. Neoplasia 13:676–684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • David, Rachel (2013) Development: G9A covers all bases. Nat Rev Mol Cell Biol 14(1):5–5

    Article  CAS  PubMed  Google Scholar 

  • Ebbers L, Runge K, Nothwang HG (2016) Differential patterns of histone methylase EHMT2 and its catalyzed histone modifications H3K9me1 and H3K9me2 during maturation of central auditory system. Cell & Tissue Research 365(2):247–264

    Article  CAS  Google Scholar 

  • Fetoni AR, Picciotti PM, Paludetti G, Troiani D (2011) Pathogenesis of presbycusis in animal models: a review. Exp Gerontol 46:413–425

    Article  PubMed  Google Scholar 

  • Fetoni AR, Troiani D, Petrosini L, Paludetti G (2015) Cochlear injury and adaptive plasticity of the auditory cortex. Front Aging Neurosci 7:8

    Article  PubMed  PubMed Central  Google Scholar 

  • Fetoni AR, Paciello F, Rolesi R, Paludetti G, Troiani D (2019) Targeting dysregulation of redox homeostasis in noise-induced hearing loss: oxidative stress and ROS signaling. Free Radic Biol Med 135:46–59

    Article  CAS  PubMed  Google Scholar 

  • Guptaagarwal S, Franklin A, Deramus T, Wheelock M, Davis R, Mcmahon L, Lubin F (2012) G9a/GLP histone lysine Dimethyltransferase complex activity in the hippocampus and the entorhinal cortex is required for gene activation and silencing during memory consolidation. J Neurosci 32:5440–5453

    Article  CAS  Google Scholar 

  • Lee MC, Kuo YY, Chou WC, Hou HA, Hsiao M, Tien HF (2014) Gfi-1 is the transcriptional repressor of SOCS1 in acute myeloid leukemia cells. J Leukoc Biol 95(1):105–115

    Article  PubMed  Google Scholar 

  • Loyola A, Bonaldi T, Roche D, Imhof A, Almouzni G (2006) PTMs on H3 variants before chromatin assembly potentiate their final epigenetic state. Mol Cell 24(2):309–316

    Article  CAS  PubMed  Google Scholar 

  • Maze I, Covington HE, Dietz DM, LaPlant Q, Renthal W, Russo SJ, Mechanic M, Mouzon E, Neve RL, Haggarty SJ (2010) Essential role of the histone methyltransferase G9a in cocaine-induced plasticity. Science 327(5962):213–216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maze I, Dietz David M, Kennedy Pamela J, Sillivan Stephanie E, Bagot Rosemary C, Gustavo T, Hurd Yasmin L, Ming-Hu H, Nestler Eric J (2014) G9a influences neuronal subtype specification in striatum. Nat Neurosci 17(4):533–539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murat U, Nil DZ, Yusuf V (2005) N-acetyltransferase 2 gene polymorphism and presbycusis. Laryngoscope 115:2238–2241

    Article  Google Scholar 

  • Ning D, Zhou H, Esteve PO, Hang GC, Boyer TG (2008) Mediator links epigenetic silencing of neuronal gene expression with X-linked mental retardation. Mol Cell 31:347–359

    Article  Google Scholar 

  • Noh KM, Hwang JY, Follenzi A, Athanasiadou R, Miyawaki T, Greally JM, Bennett MVL, Zukin RS (2012) Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death. Proc Natl Acad Sci U S A 109(16):5928–5929

    Article  CAS  Google Scholar 

  • Pang J, Xiong H, Ou Y, Yang H, Xu Y, Chen S, Lai L, Ye Y, Su Z, Lin H, Huang Q, Xu X, Zheng Y (2019) SIRT1 protects cochlear hair cell and delays age-related hearing loss via autophagy. Neurobiol Aging 80:127–137

    Article  CAS  PubMed  Google Scholar 

  • Parthasarathy A, Bartlett EL, Kujawa SG (2019) Age-related changes in neural coding of envelope cues: peripheral declines and central compensation. Neuroscience 407:21–31

    Article  CAS  PubMed  Google Scholar 

  • Pinheiro I, Margueron R, Shukeir N, Eisold M, Fritzsch C, Richter FM, Mittler G, Genoud C, Goyama S, Kurokawa M, Son J, Reinberg D, Lachner M, Jenuwein T (2012) Prdm3 and Prdm16 are H3K9me1 methyltransferases required for mammalian heterochromatin integrity. Cell 150(5):948–960

    Article  CAS  PubMed  Google Scholar 

  • Rodenas-Ruano A, Chávez AE, Cossio MJ, Castillo PE, Zukin RS (2012) REST-dependent epigenetic remodeling promotes the developmental switch in synaptic NMDA receptors. Nat Neurosci 15(10):1382–1390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schaefer A, Sampath SC, Intrator A, Min A, Greengard P (2009) Control of cognition and adaptive behavior by the GLP/G9a epigenetic suppressor complex. Neuron 64(5):678–691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Someya S, Yamasoba T, Kujoth GC, Pugh TD, Weindruch R, Tanokura M, Prolla TA (2008) The role of mtDNA mutations in the pathogenesis of age-related hearing loss in mice carrying a mutator DNA polymerase gamma. Neurobiol Aging 29(7):1080–1092

    Article  CAS  PubMed  Google Scholar 

  • Son HJ, Kim J-Y, Hahn Y, Seo S-B (2012) Negative regulation of JAK2 by H3K9 methyltransferase G9a in leukemia. Molecular & Cellular Biology 32:3681–3694

    Article  CAS  Google Scholar 

  • Subbanna S, Shivakumar M, Umapathy NS, Saito M, Mohan PS, Kumar A, Nixon RA, Verin AD, Psychoyos D, Basavarajappa BS (2013) G9a-mediated histone methylation regulates ethanol-induced neurodegeneration in the neonatal mouse brain. Neurobiol Dis 54:475–485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun W, Deng A, Jayaram A, Gibson B (2012a) Noise exposure enhances auditory cortex responses related to hyperacusis behavior. Brain Res 1485:108–116

    Article  CAS  PubMed  Google Scholar 

  • Sun H, Maze I, Dietz DM, Scobie KN, Kennedy PJ, Damez-Werno D, Neve RL, Zachariou V, Shen L, Nestler EJ (2012b) Morphine epigenomically regulates behavior through alterations in histone H3 lysine 9 Dimethylation in the nucleus Accumbens. J Neurosci 32:17454–17464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tachibana M (2002) G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev 16(14):1779–1791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tachibana M, Nozaki M, Takeda N, Shinkai Y (2007) Functional dynamics of H3K9 methylation during meiotic prophase progression. EMBO J 26(14):3346–3359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takada Y, Naruse C, Costa Y, Shirakawa T, Tachibana M, Sharif J, Kezuka-Shiotani F, Kakiuchi D, Masumoto H, Shinkai Y (2011) HP1γ links histone methylation marks to meiotic synapsis in mice. Development 138(19):4207–4217

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Xu S, Lee JE, Baldridge A, Ge K (2012) Histone H3K9 methyltransferase G9a represses PPARγ expression and adipogenesis. EMBO J 32:45–59

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhong C, Fu Y, Pan W, Yu J, Wang J (2019) Atoh1 and other related key regulators in the development of auditory sensory epithelium in the mammalian inner ear: function and interplay. Dev Biol 446(2):133–141

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This project was supported by grants from Chongqing Natural Science Foundation (Grant Serial Numbers: cstc2018jcyjAX0229).

Author information

Authors and Affiliations

Authors

Contributions

An-chun Deng designed and supervised the study. Qian Li wrote the manuscript and produced figures. Yang-hong Xiang, Xiao-jun Liang, Yun Zhang, Peng-peng Zhao, Min Wang, Xiao-min Bao and Xian-bai Zhu collected and analyzed data.

Corresponding author

Correspondence to An-chun Deng.

Ethics declarations

All animal experiments were performed according to the Guide for the Care and Use of Laboratory Animals 8th Edition. The study was approved by the Ethics Committee of Army Medical University (Chongqing, China).

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Q., Xiang, Yh., Liang, Xj. et al. Expression of G9a in Auditory Cortex Is Downregulated in a Rat Model of Age-Related Hearing Loss. J Mol Neurosci 71, 409–418 (2021). https://doi.org/10.1007/s12031-020-01663-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-020-01663-z

Keywords

Navigation