Plasticity of DNA methylation in a nerve injury model of pain

Meike Gölzenleuchter, Rahul Kanwar, Manal Zaibak, Fadi Al Saiegh, Theresa Hartung, Jana Klukas, Regenia L. Smalley, Julie M Cunningham, Maria E. Figueroa, Gary P. Schroth, Terry M Therneau, Michaela S. Banck, Andreas S Beutler

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The response of the peripheral nervous system (PNS) to injury may go together with alterations in epigenetics, a conjecture that has not been subjected to a comprehensive, genome-wide test. Using reduced representation bisulfite sequencing, we report widespread remodeling of DNA methylation in the rat dorsal root ganglion (DRG) occurring within 24 h of peripheral nerve ligation, a neuropathy model of allodynia. Significant (P < 10-4) cytosine hyper- and hypo-methylation was found at thousands of CpG sites. Remodeling occurred outside of CpG islands. Changes affected genes with known roles in the PNS, yet methylome remodeling also involved genes that were not linked to neuroplasticity by prior evidence. Consistent with emerging models relying on genome-wide methylation and RNA-seq analysis of promoter regions and gene bodies, variation of methylation was not tightly linked with variation of gene expression. Furthermore, approximately 44% of the dynamically changed CpGs were located outside of genes. We compared their positions with the intergenic, tissue-specific differentially methylated CpGs (tDMCs) of an independent experimental set consisting of liver, spleen, L4 control DRG, and muscle. Dynamic changes affected those intergenic CpGs that were different between tissues (P < 10-15) and almost never the invariant portion of the methylome (those CpGs that were identical across all tissues). Our findings—obtained in mixed tissue—show that peripheral nerve injury leads to methylome remodeling in the DRG. Future studies may address which of the cell types found in the DRG, such as specific groups of neurons or non-neuronal cells are affected by which aspect of the observed methylome remodeling.

Original languageEnglish (US)
Pages (from-to)200-212
Number of pages13
JournalEpigenetics
Volume10
Issue number3
DOIs
StatePublished - Jan 26 2015

Fingerprint

Spinal Ganglia
DNA Methylation
Methylation
Pain
Peripheral Nervous System
Wounds and Injuries
Genes
Genome
Nervous System Trauma
Peripheral Nerve Injuries
CpG Islands
Neuronal Plasticity
Cytosine
Hyperalgesia
Peripheral Nerves
Genetic Promoter Regions
Epigenomics
Ligation
Spleen
RNA

Keywords

  • Dorsal root ganglion
  • Methylation
  • Nervous system
  • Pain
  • Peripheral
  • Rat
  • RRBS
  • Spinal nerve ligation

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Gölzenleuchter, M., Kanwar, R., Zaibak, M., Al Saiegh, F., Hartung, T., Klukas, J., ... Beutler, A. S. (2015). Plasticity of DNA methylation in a nerve injury model of pain. Epigenetics, 10(3), 200-212. https://doi.org/10.1080/15592294.2015.1006493

Plasticity of DNA methylation in a nerve injury model of pain. / Gölzenleuchter, Meike; Kanwar, Rahul; Zaibak, Manal; Al Saiegh, Fadi; Hartung, Theresa; Klukas, Jana; Smalley, Regenia L.; Cunningham, Julie M; Figueroa, Maria E.; Schroth, Gary P.; Therneau, Terry M; Banck, Michaela S.; Beutler, Andreas S.

In: Epigenetics, Vol. 10, No. 3, 26.01.2015, p. 200-212.

Research output: Contribution to journalArticle

Gölzenleuchter, M, Kanwar, R, Zaibak, M, Al Saiegh, F, Hartung, T, Klukas, J, Smalley, RL, Cunningham, JM, Figueroa, ME, Schroth, GP, Therneau, TM, Banck, MS & Beutler, AS 2015, 'Plasticity of DNA methylation in a nerve injury model of pain', Epigenetics, vol. 10, no. 3, pp. 200-212. https://doi.org/10.1080/15592294.2015.1006493
Gölzenleuchter 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 Jan 26;10(3):200-212. https://doi.org/10.1080/15592294.2015.1006493
Gölzenleuchter, Meike ; Kanwar, Rahul ; Zaibak, Manal ; Al Saiegh, Fadi ; Hartung, Theresa ; Klukas, Jana ; Smalley, Regenia L. ; Cunningham, Julie M ; Figueroa, Maria E. ; Schroth, Gary P. ; Therneau, Terry M ; Banck, Michaela S. ; Beutler, Andreas S. / Plasticity of DNA methylation in a nerve injury model of pain. In: Epigenetics. 2015 ; Vol. 10, No. 3. pp. 200-212.
@article{96b7ef398e6d4a5f8220d53db35ec429,
title = "Plasticity of DNA methylation in a nerve injury model of pain",
abstract = "The response of the peripheral nervous system (PNS) to injury may go together with alterations in epigenetics, a conjecture that has not been subjected to a comprehensive, genome-wide test. Using reduced representation bisulfite sequencing, we report widespread remodeling of DNA methylation in the rat dorsal root ganglion (DRG) occurring within 24 h of peripheral nerve ligation, a neuropathy model of allodynia. Significant (P < 10-4) cytosine hyper- and hypo-methylation was found at thousands of CpG sites. Remodeling occurred outside of CpG islands. Changes affected genes with known roles in the PNS, yet methylome remodeling also involved genes that were not linked to neuroplasticity by prior evidence. Consistent with emerging models relying on genome-wide methylation and RNA-seq analysis of promoter regions and gene bodies, variation of methylation was not tightly linked with variation of gene expression. Furthermore, approximately 44{\%} of the dynamically changed CpGs were located outside of genes. We compared their positions with the intergenic, tissue-specific differentially methylated CpGs (tDMCs) of an independent experimental set consisting of liver, spleen, L4 control DRG, and muscle. Dynamic changes affected those intergenic CpGs that were different between tissues (P < 10-15) and almost never the invariant portion of the methylome (those CpGs that were identical across all tissues). Our findings—obtained in mixed tissue—show that peripheral nerve injury leads to methylome remodeling in the DRG. Future studies may address which of the cell types found in the DRG, such as specific groups of neurons or non-neuronal cells are affected by which aspect of the observed methylome remodeling.",
keywords = "Dorsal root ganglion, Methylation, Nervous system, Pain, Peripheral, Rat, RRBS, Spinal nerve ligation",
author = "Meike G{\"o}lzenleuchter and Rahul Kanwar and Manal Zaibak and {Al Saiegh}, Fadi and Theresa Hartung and Jana Klukas and Smalley, {Regenia L.} and Cunningham, {Julie M} and Figueroa, {Maria E.} and Schroth, {Gary P.} and Therneau, {Terry M} and Banck, {Michaela S.} and Beutler, {Andreas S}",
year = "2015",
month = "1",
day = "26",
doi = "10.1080/15592294.2015.1006493",
language = "English (US)",
volume = "10",
pages = "200--212",
journal = "Epigenetics",
issn = "1559-2294",
publisher = "Landes Bioscience",
number = "3",

}

TY - JOUR

T1 - Plasticity of DNA methylation in a nerve injury model of pain

AU - Gölzenleuchter, Meike

AU - Kanwar, Rahul

AU - Zaibak, Manal

AU - Al Saiegh, Fadi

AU - Hartung, Theresa

AU - Klukas, Jana

AU - Smalley, Regenia L.

AU - Cunningham, Julie M

AU - Figueroa, Maria E.

AU - Schroth, Gary P.

AU - Therneau, Terry M

AU - Banck, Michaela S.

AU - Beutler, Andreas S

PY - 2015/1/26

Y1 - 2015/1/26

N2 - The response of the peripheral nervous system (PNS) to injury may go together with alterations in epigenetics, a conjecture that has not been subjected to a comprehensive, genome-wide test. Using reduced representation bisulfite sequencing, we report widespread remodeling of DNA methylation in the rat dorsal root ganglion (DRG) occurring within 24 h of peripheral nerve ligation, a neuropathy model of allodynia. Significant (P < 10-4) cytosine hyper- and hypo-methylation was found at thousands of CpG sites. Remodeling occurred outside of CpG islands. Changes affected genes with known roles in the PNS, yet methylome remodeling also involved genes that were not linked to neuroplasticity by prior evidence. Consistent with emerging models relying on genome-wide methylation and RNA-seq analysis of promoter regions and gene bodies, variation of methylation was not tightly linked with variation of gene expression. Furthermore, approximately 44% of the dynamically changed CpGs were located outside of genes. We compared their positions with the intergenic, tissue-specific differentially methylated CpGs (tDMCs) of an independent experimental set consisting of liver, spleen, L4 control DRG, and muscle. Dynamic changes affected those intergenic CpGs that were different between tissues (P < 10-15) and almost never the invariant portion of the methylome (those CpGs that were identical across all tissues). Our findings—obtained in mixed tissue—show that peripheral nerve injury leads to methylome remodeling in the DRG. Future studies may address which of the cell types found in the DRG, such as specific groups of neurons or non-neuronal cells are affected by which aspect of the observed methylome remodeling.

AB - The response of the peripheral nervous system (PNS) to injury may go together with alterations in epigenetics, a conjecture that has not been subjected to a comprehensive, genome-wide test. Using reduced representation bisulfite sequencing, we report widespread remodeling of DNA methylation in the rat dorsal root ganglion (DRG) occurring within 24 h of peripheral nerve ligation, a neuropathy model of allodynia. Significant (P < 10-4) cytosine hyper- and hypo-methylation was found at thousands of CpG sites. Remodeling occurred outside of CpG islands. Changes affected genes with known roles in the PNS, yet methylome remodeling also involved genes that were not linked to neuroplasticity by prior evidence. Consistent with emerging models relying on genome-wide methylation and RNA-seq analysis of promoter regions and gene bodies, variation of methylation was not tightly linked with variation of gene expression. Furthermore, approximately 44% of the dynamically changed CpGs were located outside of genes. We compared their positions with the intergenic, tissue-specific differentially methylated CpGs (tDMCs) of an independent experimental set consisting of liver, spleen, L4 control DRG, and muscle. Dynamic changes affected those intergenic CpGs that were different between tissues (P < 10-15) and almost never the invariant portion of the methylome (those CpGs that were identical across all tissues). Our findings—obtained in mixed tissue—show that peripheral nerve injury leads to methylome remodeling in the DRG. Future studies may address which of the cell types found in the DRG, such as specific groups of neurons or non-neuronal cells are affected by which aspect of the observed methylome remodeling.

KW - Dorsal root ganglion

KW - Methylation

KW - Nervous system

KW - Pain

KW - Peripheral

KW - Rat

KW - RRBS

KW - Spinal nerve ligation

UR - http://www.scopus.com/inward/record.url?scp=84925337444&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84925337444&partnerID=8YFLogxK

U2 - 10.1080/15592294.2015.1006493

DO - 10.1080/15592294.2015.1006493

M3 - Article

VL - 10

SP - 200

EP - 212

JO - Epigenetics

JF - Epigenetics

SN - 1559-2294

IS - 3

ER -