Abstract
Persistent pain is sustained by maladaptive changes in gene transcription resulting in altered function of the relevant circuits; therapies are still unsatisfactory. The epigenetic mechanisms and affected genes linking nociceptive activity to transcriptional changes and pathological sensitivity are unclear. Here, we found that, among several histone deacetylases (HDACs), synaptic activity specifically affects HDAC4 in murine spinal cord dorsal horn neurons. Noxious stimuli that induce long-lasting inflammatory hypersensitivity cause nuclear export and inactivation of HDAC4. The development of inflammation-associated mechanical hypersensitivity, but neither acute nor basal sensitivity, is impaired by the expression of a constitutively nuclear localized HDAC4 mutant. Next generation RNA-sequencing revealed an HDAC4-regulated gene program comprising mediators of sensitization including the organic anion transporter OAT1, known for its renal transport function. Using pharmacological and molecular tools to modulate OAT1 activity or expression, we causally link OAT1 to persistent inflammatory hypersensitivity in mice. Thus, HDAC4 is a key epigenetic regulator that translates nociceptive activity into sensitization by regulating OAT1, which is a potential target for pain-relieving therapies.
Highlights
Persistent pain is sustained by maladaptive changes in gene transcription resulting in altered function of the relevant circuits; therapies are still unsatisfactory
Following treatment of primary spinal cord neurons with the gamma-aminobutyric acid-A-receptor antagonist bicuculline (Bic) to induce bursts of synaptic activity, and consistent with our observations in hippocampal neurons[18], we found that members of class I (HDAC1 and 3), class IIb (HDAC10), and class IV (HDAC11) did not change their subcellular distribution (Supplementary Fig. 1a, Fig. 1b)
In line with a functional relevance for the redistribution of HDAC4 in cultured spinal cord neurons, synaptic activity induced a significant increase of acetylated histone 3-Lys[9] (AcH3) levels whereas total histone 3 levels remained constant (Supplementary Fig. 1f, g)
Summary
Persistent pain is sustained by maladaptive changes in gene transcription resulting in altered function of the relevant circuits; therapies are still unsatisfactory. The epigenetic mechanisms and affected genes linking nociceptive activity to transcriptional changes and pathological sensitivity are unclear. Within the heterogeneous group of epigenetic players, DNA methyltransferases and histone deacetylases (HDACs) are prominent mediators of adaptive processes in the CNS owing to their capacity to translate incoming synaptic activity into long-lasting transcriptional responses. There is no information on the regulation in spinal cord circuits of a fundamental aspect modulating the activity of class IIa HDACs, namely their subcellular localization, and how its potential alteration may functionally contribute to chronic pain. Most importantly from a mechanistic viewpoint, the identity of genes underpinning central sensitization and controlled by class IIa HDACs in spinal cord neurons in pathological pain is still elusive
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