表觀遺傳調控基因表現在慢性疼痛中所扮演之角色

Abstract

表觀遺傳修飾泛指影響基因表現的各種後天轉錄修飾，例如： DNA 甲基化和組蛋白修飾作用，已被證實可影響神經活性、突觸塑性、學習及記憶固化。近年來，雖然已有證據支持神經系統中傷害感受性基因的表觀遺傳修飾與慢性疼痛發展進程相關，但是詳細的調控機制目前仍有待釐清。本論文證實，脊髓上十一位易位甲基胞嘧啶雙加氧酶 1 (Tet1) 所媒介的 DNA 去甲基化作用 (DNA demethylation) ，能影響腦源性神經營養因子 (BDNF) 基因之轉錄和表現，進而影響神經病理性疼痛發展。此外，組蛋白去乙醯化蛋白酶 4 之細胞質滯留 (HDAC4 cytoplasmic retention) 及溴結構域蛋白 4 (Brd4) 所依賴性的乙醯化作用 (acetylation) ，分別調控脊髓背角上高遷移率族蛋白 1 (HMGB1) 和背根神經節上電壓調控鈉離子通道 1.7 (Nav1.7) 之轉錄作用，進而媒介神經病理性和發炎性之慢性疼痛發展。另一方面，透過椎管內注射退黑激素 (melatonin) 可反轉組蛋白去乙醯化蛋白酶 4 之細胞質滯留依賴性乙醯化作用，減緩疼痛行為；椎管內前處理退黑激素受體第二型 (MT2) 的拮抗劑，則可反轉上述退黑激素的效用。綜合上述，我們的研究結果可以說明，去甲基化或乙醯化此兩種表觀遺傳修飾作用，皆能透過影響傷害感受性基因表現，參與慢性疼痛發展進程。此外，退黑激素可透過退黑激素受體第二型，反轉乙醯化標的基因，有效減緩疼痛行為。因此，退黑激素可能為表觀遺傳修飾治療疼痛的方針。

Epigenetic processes, such as DNA methylation and histone modification, have significant effects on neuronal activity, synaptic plasticity, learning, and memory consolidation. Evidence is starting to emerge supporting the role of epigenetic mechanisms at nociceptive genes in the nervous system relevant to chronic pain processing. Nevertheless, the research in this area remains in its infancy. Here, we identified that spinal ten-eleven translocation methylcytosine dioxygenase 1 (Tet1)-mediated DNA demethylation of brain-derived neurotropic factor (BDNF), which facilitate gene transcription and expression, initiate behavioral nociception. Moreover, we also found that histone deacetylase 4 (HDAC4) cytoplasmic retention- and bromodomain-containing protein 4 (Brd4)-dependent acetylation, are responsible for direct transcriptional control of high-mobility group protein B1 (HMGB1) in the dorsal horn and voltage-gated sodium channel 1.7 (Nav1.7) in the dorsal root ganglia, as an epigenetic mechanism mediating pain hypersensitivity caused by neuropathic and inflammatory insults. Notably, intrathecal melatonin injection ameliorated developed pain hypersensitivity by reversing the HDAC4 cytoplasmic retention-dependent promoter acetylation in the dorsal horn neurons. Furthermore, the effects caused by melatonin were blocked by pretreatment with a MT2 receptor-selective antagonist. Collectively, our findings strong suggest that DNA demethylation and histone acetylation are important epigenetic mechanisms impacting the expression of nociceptive genes in chronic pain states. And, melatonin/MT2 signaling remedies pain hypersensitivity by epigenetically reversing histone acetylation of the target gene. These results suggest melatonin as an epigenetic promising therapy for treating chronic pain.