查看“EZH1”的源代码

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            <strong>[[EZH1]]</strong>（<strong>[[Enhancer of zeste homolog 1]]</strong>）是一种关键的<strong>[[组蛋白甲基转移酶]]</strong>，是<strong>[[PRC2复合物]]</strong>（[[Polycomb Repressive Complex 2]]）的两个催化亚基之一。作为[[EZH2]]的同源蛋白，[[EZH1]]通过对[[组蛋白H3]]第27位赖氨酸进行甲基化（<strong>[[H3K27me1/2/3]]</strong>），介导基因表达的[[表观遗传]]抑制。与主要在增殖细胞中表达的[[EZH2]]不同，[[EZH1]]在非增殖和[[分化]]细胞中亦有广泛表达，并具有维持[[造血干细胞]]稳态及调控[[染色质]]结构的独特功能。在临床肿瘤学中，[[EZH1]]常作为肿瘤在[[EZH2抑制剂]]治疗后产生[[获得性耐药]]的补偿性通路。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">[[EZH1]]</div>
            <div style="font-size: 0.75em; opacity: 0.85; margin-top: 4px;">组蛋白甲基转移酶 · 点击展开</div>
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                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">染色体位置：17q21.2</div>
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                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">2145</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[HGNC]]ID</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">3526</td>
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                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">Q92800</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">蛋白结构域</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">[[SET结构域]]</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[分子量]]</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">约85.3kDa</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569;">主要相互作用</th>
                    <td style="padding: 12px; color: #0f172a;">[[EED]]•[[SUZ12]]</td>
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    <h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">分子生物学机制</h2>
    
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        [[EZH1]]在[[染色质]]重塑和转录调控中扮演着复杂且不可替代的角色：
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        <li style="margin-bottom: 12px;"><strong>PRC2组分与甲基化：</strong>[[EZH1]]与[[EED]]、[[SUZ12]]和[[RBBP4]]结合形成核心[[PRC2复合物]]。其[[SET结构域]]利用[[SAM]]（[[S-腺苷甲硫氨酸]]）作为甲基供体，催化[[组蛋白H3]]赖氨酸27位的[[甲基化]]。</li>
        <li style="margin-bottom: 12px;"><strong>与[[EZH2]]的功能分化：</strong>相比于[[EZH2]]强大的三甲基化（[[H3K27me3]]）能力，[[EZH1]]的催化效率较低，但在紧致[[染色质]]和维持基因[[长期沉默]]方面具有优势。</li>
        <li style="margin-bottom: 12px;"><strong>代偿性上调：</strong>在[[血液系统肿瘤]]中，当[[EZH2]]被抑制时，肿瘤细胞常代偿性上调[[EZH1]]的表达，以维持关键癌基因的表观状态。</li>
        <li style="margin-bottom: 12px;"><strong>独立于PRC2的功能：</strong>新兴研究表明，[[EZH1]]在某些条件下可参与转录激活，尤其是在[[核糖体]]生物合成及非典型信号通路中。</li>
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                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">病理领域</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #475569;">EZH1 表达特征</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #1e40af;">临床意义</th>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[外周T细胞淋巴瘤]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">普遍过表达</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">维持[[T细胞]]恶性增殖，是[[双靶点抑制]]的首选指征。</td>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[骨髓增生异常综合征]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">调控失衡</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">与[[造血干细胞]]的过早衰竭或恶性转化相关。</td>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[实体瘤耐药]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">代偿性高表达</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">导致单一[[EZH2]]靶向药失效的关键因素。</td>
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    <h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">诊疗策略：双重抑制的突破</h2>
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        针对[[EZH1]]与[[EZH2]]的功能冗余性，当前的精准治疗策略倾向于<strong>[[双靶点抑制]]</strong>：
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        <li style="margin-bottom: 12px;"><strong>[[瓦美妥司他]] (Valemetostat)：</strong>作为全球首个获批的[[EZH1/2]]双抑制剂，它能同时结合两个亚基的[[SET结构域]]，彻底阻断[[H3K27me3]]的再生，显著提升了[[复发/难治型]]淋巴瘤的治疗效果。</li>
        <li style="margin-bottom: 12px;"><strong>[[表观遗传重塑]]：</strong>通过抑制[[EZH1]]，可重新激活被抑制的[[抑癌基因]]。这种疗法正探索与[[化疗]]或[[免疫检查点抑制剂]]联用，以逆转肿瘤的[[免疫冷环境]]。</li>
        <li style="margin-bottom: 12px;"><strong>安全性考量：</strong>虽然[[EZH1]]在正常细胞中有表达，但双抑制剂在推荐剂量下展现了良好的治疗窗口，主要需关注[[血液学毒性]]（如[[血小板减少]]）。</li>
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            <li style="margin-bottom: 8px;"><strong>[[PRC2]]：</strong>由[[EZH1/2]]等组成的蛋白质复合体，是高等真核生物基因沉默的核心。</li>
            <li style="margin-bottom: 8px;"><strong>[[H3K27me3]]：</strong>表征抑制性染色质状态的经典[[组蛋白标记]]。</li>
            <li style="margin-bottom: 8px;"><strong>[[SET结构域]]：</strong>具催化活性的结构域，得名于[[Drosophila]]中的三个蛋白（Su(var)3-9, E(z), Trithorax）。</li>
            <li style="margin-bottom: 8px;"><strong>[[瓦美妥司他]]：</strong>[[第一三共]]研发的双靶点明星药物。</li>
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        <span style="color: #0f172a; font-weight: bold; font-size: 1.05em; display: inline-block; margin-bottom: 15px;">学术参考文献与权威点评</span>
        
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            [1] <strong>Margueron R, et al. (2008).</strong> <em>EZH1 and EZH2 maintain repressive chromatin through different mechanisms.</em> <strong>[[Molecular Cell]]</strong>.[Academic Review]<br>
            <span style="color: #475569;">[权威点评]：该项研究首次从生化层面界定了EZH1与EZH2在染色质调节中的分工与差异。</span>
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            [2] <strong>Izutsu K, et al. (2023).</strong> <em>Valemetostat in patients with relapsed or refractory adult T-cell leukemia/lymphoma.</em> <strong>[[The Lancet Oncology]]</strong>.<br>
            <span style="color: #475569;">[核心价值]：该研究证实了同时靶向EZH1/2是克服血液肿瘤表观遗传耐药的有效临床路径。</span>
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            [[EZH1]] 诊疗生态 · 知识图谱
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">关联靶点</td>
                <td style="padding: 10px 15px; color: #334155;">[[EZH2]]•[[EED]]•[[SUZ12]]•[[PRC2]]•[[DNMT]]</td>
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">治疗药物</td>
                <td style="padding: 10px 15px; color: #334155;">[[瓦美妥司他]]•[[DS-3201]]•[[他泽司他]] (Tazemetostat)</td>
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">战略实体</td>
                <td style="padding: 10px 15px; color: #334155;">[[第一三共]]•[[PMDA]]•[[FDA]]•[[NMPA]]</td>
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">研究前沿</td>
                <td style="padding: 10px 15px; color: #334155;">[[克服EZH2突变耐药]]•[[表观遗传与免疫疗法联合]]•[[非典型转录激活功能研究]]</td>
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