Ischemic insults promote epigenetic reprogramming of μ opioid receptor expression in hippocampal neurons
Ischemic insults promote epigenetic reprogramming of μ opioid receptor expression in hippocampal neurons
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DOI：
10.1073/pnas.0611704104
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发表时间：
2007-03-06
影响因子：
11.1
通讯作者：
Zukin, R. Suzanne
中科院分区：
文献类型：
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作者：
Formisano, Luigi;Noh, Kyung-Min;Zukin, R. Suzanne
短暂性全脑缺血是一种神经元损伤，可诱导海马CA 1区锥体神经元延迟性、选择性死亡。缺血诱导的细胞死亡的潜在机制是基因沉默转录因子REST（阻遏物元件-1沉默转录因子）/NRSF（神经元限制性沉默因子）的激活和注定死亡的CA 1神经元中AMPA受体亚基GluR 2的REST依赖性抑制。在这里，我们表明，REST调节一个额外的基因靶点，OPRM 1（μ阿片受体1或莫尔-1）。MORs在CA 1的篮状细胞和其他抑制性中间神经元中大量表达。通过实时定量RT-PCR、Western印迹和ChIP评估，全脑缺血诱导特异于选择性易损区CA 1的莫尔-1 mRNA和蛋白表达显著降低。我们进一步表明，OPRM 1基因沉默是REST依赖性的，并通过表观遗传修饰发生。缺血促进核心组蛋白H3和H4的脱乙酰化以及组蛋白H3在莫尔-1启动子上的赖氨酸-9（H3-K9）处的二甲基化，这是表观遗传基因沉默的特征。通过体外海马脑片给予反义寡核苷酸或体内大鼠注射莫尔拮抗剂纳洛酮，急性敲低莫尔-1基因表达，可保护CA 1锥体神经元免受缺血诱导的死亡。这些发现暗示MORs参与了缺血诱导的CA 1锥体神经元死亡，并记录了CA 1抑制性中间神经元中OPRM 1表达的表观遗传重塑。
Transient global ischemia is a neuronal insult that induces delayed, selective death of hippocampal CA1 pyramidal neurons. A mechanism underlying ischemia-induced cell death is activation of the gene silencing transcription factor REST (repressor element-1 silencing transcription factor)/NRSF (neuron-restrictive silencing factor) and REST-dependent suppression of the AMPA receptor subunit GluR2 in CA1 neurons destined to die. Here we show that REST regulates an additional gene target, OPRM 1 (mu opioid receptor 1 or MOR-1). MORs are abundantly expressed by basket cells and other inhibitory interneurons of CA1. Global ischemia induces a marked decrease in MOR-1 mRNA and protein expression that is specific to the selectively vulnerable area CA1, as assessed by quantitative real-time RT-PCR, Western blotting, and ChlP. We further show that OPRM1 gene silencing is REST-dependent and occurs via epigenetic modifications. Ischemia promotes deacetylation of core histone proteins H3 and H4 and dimethylation of histone H3 at lysine-9 (H3-K9) over the MOR-1 promoter, an signature of epigenetic gene silencing. Acute knockdown of MOR-1 gene expression by administration of antisense oligodeoxynucleotides to hippocampal slices in vitro or injection of the MOR antagonist naloxone to rats in vivo affords protection against ischemia-induced death of CA1 pyramidal neurons. These findings implicate MORs in ischemia-induced death of CA1 pyramidal neurons and document epigenetic remodeling of expression of OPRM1 in CA1 inhibitory interneurons.