DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons

Zhao, Jian; Liang, Lingli; Gu, Xiechong; Li, Zhisong; Wu, Shaogen; Sun, Linlin; Atianjoh, Fidelis E.; Feng, Jian; Mo, Kai; Jia, Shushan; Lutz, Brianna Marie; Bekker, Alex; Nestler, Eric J.; Tao, Yuan Xiang

doi:10.1038/ncomms14712

Cited by 167 publications

(273 citation statements)

References 59 publications

(121 reference statements)

Supporting

Mentioning

258

Contrasting

Order By: Relevance

“…DRG microinjection was carried out as described [15;49]. Briefly, a midline skin incision was made in the lower lumbar back region, and the L5 DRG in rats or L4 DRG in mice was exposed.…”

Section: Methodsmentioning

confidence: 99%

“…Thermal test was carried out as previously described [15;46;49]. Briefly, each rat was placed in a plexiglas chamber on an elevated grid and acclimated for 30 minutes before behavioral test.…”

Section: Methodsmentioning

confidence: 99%

“…Ratios of ipsilateral-side mRNA levels to contralateral-side mRNA levels were calculated using the ΔCt method (2 −ΔΔCt ). All data were normalized to Gapdh , which has been demonstrated to be stable even after peripheral nerve injury insult [15;49]. …”

Section: Methodsmentioning

confidence: 99%

“…Tissues were prepared as previously described [15;49]. Briefly, DRGs were homogenized with ice-cold lysis buffer (10 mM Tris, 5 mM EGTA, 0.5% Triton X-100, 2 mM benzamidine, 0.1 mM phenylmethylsulfonyl fluoride, 40 μM leupeptin, 150 mM NaCl).…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Nerve injury–induced epigenetic silencing of opioid receptors controlled by DNMT3a in primary afferent neurons

Sun

Zhao

et al. 2017

Pain

Self Cite

View full text Add to dashboard Cite

Opioids are the gold standard for pharmacological treatment of neuropathic pain, but their analgesic effects are unsatisfactory in part due to nerve injury-induced downregulation of opioid receptors in dorsal root ganglia (DRG) neurons. How nerve injury drives such downregulation remains elusive. DNA methyltransferase-(DNMT-) triggered DNA methylation represses gene expression. We show here that blocking the nerve injury-induced increase in DRG DNMT3a (a de novo DNMT) rescued the expression of Oprm1 and Oprk1 mRNAs and their respective encoding mu opioid receptor (MOR) and kappa opioid receptor (KOR) proteins in the injured DRG. Blocking this increase also prevented the nerve injury-induced increase in DNA methylation in the promoter and 5′-untranslated region of the Oprm1 gene in the injured DRG, restored morphine or loperamide (a peripheral acting MOR preferring agonist) analgesic effects, and attenuated the development of their analgesic tolerance under neuropathic pain conditions. Mimicking this increase reduced the expression of Oprm1 and Oprk1 mRNAs and their coding MOR and KOR in DRG and augmented MOR-gated neurotransmitter release from the primary afferents. Mechanistically, DNMT3a regulation of Oprm1 gene expression required the methyl-CpG-binding protein 1, MBD1, as MBD1 knockout resulted in the decreased binding of DNMT3a to the Oprm1 gene promoter and blocked the DNMT3a-triggered repression of Oprm1 gene expression in DRG neurons. These data suggest that DNMT3a is required for nerve injury-induced and MBD1-mediated epigenetic silencing of the MOR and KOR in the injured DRG. DNMT3a inhibition may serve as a promising adjuvant therapy for opioid use in neuropathic pain management.

show abstract

“…DRG microinjection was carried out as described [15;49]. Briefly, a midline skin incision was made in the lower lumbar back region, and the L5 DRG in rats or L4 DRG in mice was exposed.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Nerve injury–induced epigenetic silencing of opioid receptors controlled by DNMT3a in primary afferent neurons

Sun

Zhao

et al. 2017

Pain

Self Cite

View full text Add to dashboard Cite

show abstract

“…Three DNA (cytosine-5)-methyltransferase (DNMT) enzymes — DNMT1, DNMT3A and DNMT3B — are responsible for catalysing this reaction. All three isoforms are expressed in DRG sensory neurons; however, DNMT3A may also be expressed in satellite glial cells in the DRG 174,175 . Generally associated with transcriptional repression, DNA methylation can be removed by methylcytosine dioxygenases (TET proteins) to activate transcription.…”

Section: Epigenetic Integration In the Nucleusmentioning

confidence: 99%

Intrinsic mechanisms of neuronal axon regeneration

2018

View full text Add to dashboard Cite

Permanent disabilities following CNS injuries result from the failure of injured axons to regenerate and rebuild functional connections with their original targets. By contrast, injury to peripheral nerves is followed by robust regeneration, which can lead to recovery of sensory and motor functions. This regenerative response requires the induction of widespread transcriptional and epigenetic changes in injured neurons. Considerable progress has been made in recent years in understanding how peripheral axon injury elicits these widespread changes through the coordinated actions of transcription factors, epigenetic modifiers and, to a lesser extent, microRNAs. Although many questions remain about the interplay between these mechanisms, these new findings provide important insights into the pivotal role of coordinated gene expression and chromatin remodelling in the neuronal response to injury.

show abstract

N⁶‐Methyladenosine Demethylase FTO Contributes to Neuropathic Pain by Stabilizing G9a Expression in Primary Sensory Neurons

et al. 2020

View full text Add to dashboard Cite

Nerve injury‐induced change in gene expression in primary sensory neurons of dorsal root ganglion (DRG) is critical for neuropathic pain genesis. N 6 ‐methyladenosine (m 6 A) modification of RNA represents an additional layer of gene regulation. Here, it is reported that peripheral nerve injury increases the expression of the m 6 A demethylase fat‐mass and obesity‐associated proteins (FTO) in the injured DRG via the activation of Runx1, a transcription factor that binds to the Fto gene promoter. Mimicking this increase erases m 6 A in euchromatic histone lysine methyltransferase 2 ( Ehmt2 ) mRNA (encoding the histone methyltransferase G9a) and elevates the level of G9a in DRG and leads to neuropathic pain symptoms. Conversely, blocking this increase reverses a loss of m 6 A sites in Ehmt2 mRNA and destabilizes the nerve injury‐induced G9a upregulation in the injured DRG and alleviates nerve injury‐associated pain hypersensitivities. FTO contributes to neuropathic pain likely through stabilizing nerve injury‐induced upregulation of G9a, a neuropathic pain initiator, in primary sensory neurons.

show abstract

DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons

Cited by 167 publications

References 59 publications

Nerve injury–induced epigenetic silencing of opioid receptors controlled by DNMT3a in primary afferent neurons

Nerve injury–induced epigenetic silencing of opioid receptors controlled by DNMT3a in primary afferent neurons

Intrinsic mechanisms of neuronal axon regeneration

N⁶‐Methyladenosine Demethylase FTO Contributes to Neuropathic Pain by Stabilizing G9a Expression in Primary Sensory Neurons

Contact Info

Product

Resources

About

DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons

Cited by 167 publications

References 59 publications

Nerve injury–induced epigenetic silencing of opioid receptors controlled by DNMT3a in primary afferent neurons

Nerve injury–induced epigenetic silencing of opioid receptors controlled by DNMT3a in primary afferent neurons

Intrinsic mechanisms of neuronal axon regeneration

N6‐Methyladenosine Demethylase FTO Contributes to Neuropathic Pain by Stabilizing G9a Expression in Primary Sensory Neurons

Contact Info

Product

Resources

About

N⁶‐Methyladenosine Demethylase FTO Contributes to Neuropathic Pain by Stabilizing G9a Expression in Primary Sensory Neurons