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.
authors.affiliation: a Departments of Anesthesiology; Oncology; and Biostatistics and Bioinformatics; Mayo Clinic , Rochester , MN USA.
authors.forename: Meike
authors.initials: M
authors.lastname: Gölzenleuchter
authors.forename: Rahul
authors.initials: R
authors.lastname: Kanwar
authors.forename: Manal
authors.initials: M
authors.lastname: Zaibak
authors.forename: Fadi
authors.initials: F
authors.lastname: Al Saiegh
authors.forename: Theresa
authors.initials: T
authors.lastname: Hartung
authors.forename: Jana
authors.initials: J
authors.lastname: Klukas
authors.forename: Regenia L
authors.initials: RL
authors.lastname: Smalley
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Maria E
authors.initials: ME
authors.lastname: Figueroa
authors.forename: Gary P
authors.initials: GP
authors.lastname: Schroth
authors.forename: Terry M
authors.initials: TM
authors.lastname: Therneau
authors.forename: Michaela S
authors.initials: MS
authors.lastname: Banck
authors.forename: Andreas S
authors.initials: AS
authors.lastname: Beutler
mesh_terms: D000818:Animals; D018899:CpG Islands; D019175:DNA Methylation; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000473:pathology*; D010146:Pain / Q000378:metabolism*; D051381:Rats; D013127:Spinal Nerves / Q000473:pathology*; D059467:Transcriptome
keywords: DRG, dorsal root ganglion; HCP, high-CpG promoter; LCP, low-CpG promoter; RRBS; RRBS, reduced representation bisulfite sequencing; SNL, spinal nerve ligation; dDMCs, dynamically differentially methylated CpGs; dorsal root ganglion; methylation; pain; peripheral nervous system; rat; spinal nerve ligation; tDMCs, tissue-specific differentially methylated CpGs; tIMCs, tissue-invariant methylated CpGs