Epigenetic control of hypersensitivity in chronic inflammatory pain by the de novo DNA methyltransferase Dnmt3a2

Abstract

Chronic pain is a pathological manifestation of neuronal plasticity supported by altered gene transcription in spinal cord neurons that results in long-lasting hypersensitivity. Recently, the concept that epigenetic regulators might be important in pathological pain has emerged, but a clear understanding of the molecular players involved in the process is still lacking. In this study, we linked Dnmt3a2, a synaptic activity-regulated de novo DNA methyltransferase, to chronic inflammatory pain. We observed that Dnmt3a2 levels are increased in the spinal cord of adult mice following plantar injection of Complete Freund’s Adjuvant, an in vivo model of chronic inflammatory pain. In vivo knockdown of Dnmt3a2 expression in dorsal horn neurons blunted the induction of genes triggered by Complete Freund’s Adjuvant injection. Among the genes whose transcription was found to be influenced by Dnmt3a2 expression in the spinal cord is Ptgs2, encoding for Cox-2, a prime mediator of pain processing. Lowering the levels of Dnmt3a2 prevented the establishment of long-lasting inflammatory hypersensitivity. These results identify Dnmt3a2 as an important epigenetic regulator needed for the establishment of central sensitization. Targeting expression or function of Dnmt3a2 may be suitable for the treatment of chronic pain.

Neuronal ensemble-specific DNA methylation strengthens engram stability

“…Taken together, these studies indicated that particularly the function of Dnmt3a is important for hippocampal memory formation. We showed that the Dnmt3a isoform, Dnmt3a2 is required for different forms of long-lasting neuronal adaptions, including long-term memory formation, and that the expression of Dnmt3a2, but not Dnmt3a1, is induced by neuronal activity and learning [12][13][14][15] . Therefore in the current study, we employed activity-dependent tools to overexpress and reinforce the function of the activity- Our results demonstrate that restricting the overexpression of Dnmt3a2 to the majority of the DG neuronal population (~75%) activated by CFC was sufficient to positively modulate the memory engram, and to specifically strengthen the memory encoding for the aversive context.…”

“…Recently developed technologies 10,11 allowed us to manipulate the levels of a DNA methyltransferase (Dnmt) specifically within hippocampal neuronal ensembles formed after contextual fear learning and to investigate the consequences of this manipulation for the strength of fear memory and stability of the engram. In particular, we elevated the levels of the de novo DNA methyltransferase (Dnmt3a2) in the dentate gyrus (DG) of the mouse hippocampus, as Dnmt3a2 expression is regulated by neuronal activity 12 and has established functions in long-lasting neuronal adaptations [13][14][15] . We showed that reinforcing DNA methylation-related mechanisms through Dnmt3a2 overexpression within memory-encoding neuronal ensembles specifically during consolidation was sufficient to strengthen contextual fear memory and the stability of the engram.…”

Time course of DNA methylation in pain conditions: From experimental models to humans

“…However, the studies agree that no alterations of DNMT3a expression exist at day 3 following CFA injection (Li et al, 2018;Qi et al, 2012). Another study by Oliveira et al (2019) found a significantly increased expression of DNMT3a2 in mouse DRG 6 hr after CFA injection with no detectable increase at day 1 or day 2 following the injection (Oliveira et al, 2019).…”

“…Chronic pain affects a great proportion of the population worldwide (Massart et al., 2016; Oliveira et al., 2019), posing major health problems affecting the quality of life of the individual (Denk & Mcmahon, 2012; Descalzi et al., 2015; Shao et al., 2017) and leading to significant socioeconomic costs (Denk & Mcmahon, 2012; Descalzi et al., 2015; Shao et al., 2017). The current, revised International Association for the Study of Pain (IASP) definition of pain is as follows: “An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” (Raja et al., 2020).…”

VEGFD Protects Retinal Ganglion Cells and, consequently, Capillaries against Excitotoxic Injury

“…The method used to construct, package, and purify rAAVs has been previously described. 89,90 rAAV serotypes 1/2 were produced by cotransfection of HEK293 cells by standard calcium phosphate precipitation. Before transfection, culture medium was replaced with fresh modified Dulbecco's medium (Iscove's modified Dulbecco's medium; Life Technologies, Carlsbad, CA, USA) containing 5% FBS without antibiotics.…”