Cancer epigenetics in the driver's seat Recent cancer genome projects unexpectedly highlighted the role of epigenetic alterations in cancer development. About half of human cancers were found to harbor mutations in chromatin proteins. In a Review, Flavahan et al. propose that chromatin and epigenetic aberrations have the potential to confer on cells the full range of oncogenic properties represented in the classic “hallmarks” depiction of cancer. They suggest that genetic, environmental, and metabolic factors can make chromatin aberrantly permissive or restrictive. Permissive chromatin creates a state of “epigenetic plasticity,” which can activate oncogene expression or cell fate changes that drive cancer development. Science, this issue p. eaal2380 BACKGROUND Chromatin is the essential medium through which transcription factors, signaling pathways, and other cues alter gene activity and cellular phenotypes. It assumes distinct conformations that reinforce regulatory activity or repression at a given locus, and reorganizes in response to appropriate intrinsic and extrinsic signals. The biologist Conrad Waddington famously conceptualized developmental specification as an epigenetic landscape in which differentiating cells proceed downhill along branching canals separated by walls that restrict cell identity. By restricting lineage-specific gene expression and phenotypes, chromatin affects the height of the walls between the canals in this epigenetic landscape. Genetic, metabolic, and environmental stimuli that disrupt chromatin alter cellular states and responses, thereby predisposing individuals to a range of common diseases. Although cancer is typically considered a genetic disease, chromatin and epigenetic aberrations play important roles in tumor potentiation, initiation, and progression. ADVANCES We discuss how the stability of chromatin, or its “resistance” to change, is precisely titrated during normal development, and we propose that deviation from this norm is a major factor in tumorigenesis. We review genetic, environmental, and metabolic stimuli that disrupt the homeostatic balance of chromatin, causing it to become aberrantly restrictive or permissive. Stimuli that increase chromatin resistance may result in a restrictive state that blocks differentiation programs. Stimuli that decrease chromatin resistance may result in a permissive state, which we refer to as epigenetic plasticity. We propose that plasticity allows premalignant or malignant cells to stochastically activate alternate gene regulatory programs and/or undergo nonphysiologic cell fate transitions. Some stochastic changes will be inconsequential “passengers”; others will confer fitness and be selected as “drivers.” As cancer cells divide, acquired epigenetic states may be maintained through cell division by DNA methylation, repressive chromatin, or gene regulatory circuits, giving rise to adaptive epiclones that fuel malignant progression. We highlight specific chromatin aberrations that confer epigenetic restriction or plasticity, and ultimately drive tumor progression via oncogene activation, tumor suppressor silencing, or adaptive cell fate transitions. Aberrations initiated by defined genetic stimuli, such as chromatin regulator gene mutations, are particularly informative regarding mechanism. Examples include gain-of-function mutations of the Polycomb repressor EZH2 that promote chromatin restriction and hinder differentiation, and metabolic enzyme mutations that disrupt the balance of DNA methylation. Changes in DNA methylation resulting from the latter have been tied to tumor suppressor silencing but may also result in stochastic insulator disruption and oncogene activation. We also carefully consider metabolic and environmental stimuli that disrupt chromatin homeostasis in the absence of genetic changes. Examples include links between folate metabolism and methylase activity, environmental factors that promote DNA hypermethylation in gastrointestinal tissues, and potential effects of microenvironmental stress on chromatin regulator expression. Purely epigenetic mechanisms may explain tumors that arise with few or no recurrent mutations, as well as heterogeneous functional phenotypes within tumors that lack genetic explanation. We conclude that chromatin and epigenetic aberrations can confer wide-ranging oncogenic properties and may fulfill all of cancer’s hallmarks. OUTLOOK Initial successes with epigenetic therapies suggest the potential of cancer epigenetics for major clinical impact. Yet realizing this promise will require a clearer understanding of epigenetic mechanisms of tumorigenesis. The identification of increasing numbers of oncogenic epigenetic lesions provides an opportunity to develop and test conceptual and mechanistic models of their functions. Progress will require new technologies for probing chromatin and epigenetic alterations with single-cell precision, as well as experimental models that faithfully recapitulate epigenetic states in tumors. We are optimistic that an improved understanding of epigenetic plasticity and restriction could advance diagnostic strategies for evaluating tumor stage and heterogeneity, and yield new therapeutic strategies for correcting epigenetic lesions or exploiting vulnerabilities of epigenetically altered cells. Epigenetic plasticity and the hallmarks of cancer. (Left) Normal chromatin and associated epigenetic mechanisms stabilize gene expression and cellular states while facilitating appropriate responses to developmental or environmental cues (blue nuclei represent normal cell state). Genetic, environmental, and metabolic insults that disrupt chromatin can lead to either restrictive or overly permissive chromatin states. (Center) Overly permissive chromatin results in epigenetic plasticity; this plasticity permits stochastic activation of alternate gene regulatory programs (red nuclei represent cancer-like cell state). (Right) Some stochastic changes will be inconsequential “passengers” while others will confer fitness and be selected as “drivers”; in this way, chromatin aberrations have the potential to fulfill each hallmark of cancer. Chromatin and associated epigenetic mechanisms stabilize gene expression and cellular states while also facilitating appropriate responses to developmental or environmental cues. Genetic, environmental, or metabolic insults can induce overly restrictive or overly permissive epigenetic landscapes that contribute to pathogenesis of cancer and other diseases. Restrictive chromatin states may prevent appropriate induction of tumor suppressor programs or block differentiation. By contrast, permissive or “plastic” states may allow stochastic oncogene activation or nonphysiologic cell fate transitions. Whereas many stochastic events will be inconsequential “passengers,” some will confer a fitness advantage to a cell and be selected as “drivers.” We review the broad roles played by epigenetic aberrations in tumor initiation and evolution and their potential to give rise to all classic hallmarks of cancer.

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表观遗传可塑性和癌症的特征

驾驶座上的癌症表观遗传学 最近的癌症基因组项目出人意料地突出了表观遗传改变在癌症发展中的作用。大约一半的人类癌症被发现在染色质蛋白中存在突变。在评论中，Flavahan 等人。提出染色质和表观遗传畸变有可能赋予细胞以癌症的经典“标志”描述中所代表的全部致癌特性。他们认为遗传、环境和代谢因素可以使染色质异常宽容或限制。许可染色质创造了一种“表观遗传可塑性”状态，它可以激活致癌基因表达或驱动癌症发展的细胞命运变化。科学，这个问题 p。eaal2380 背景染色质是必不可少的介质，通过它转录因子，信号通路和其他线索改变基因活性和细胞表型。它采用不同的构象，在特定位点加强调节活动或抑制，并根据适当的内在和外在信号进行重组。生物学家康拉德·沃丁顿 (Conrad Waddington) 著名地将发育规范概念化为一种表观遗传景观，其中分化细胞沿着由限制细胞身份的壁隔开的分支管向下移动。通过限制谱系特异性基因表达和表型，染色质会影响这种表观遗传景观中运河之间的壁的高度。破坏染色质的遗传、代谢和环境刺激会改变细胞状态和反应，从而使个体易患一系列常见疾病。尽管癌症通常被认为是一种遗传疾病，但染色质和表观遗传畸变在肿瘤增强、起始和进展中起着重要作用。进展我们讨论了染色质的稳定性，或它对变化的“抵抗力”，是如何在正常发育过程中精确滴定的，我们认为偏离这一规范是肿瘤发生的一个主要因素。我们回顾了破坏染色质稳态平衡的遗传、环境和代谢刺激，导致染色质变得异常限制或宽容。增加染色质抗性的刺激可能导致阻止分化程序的限制状态。降低染色质抗性的刺激可能会导致一种允许状态，我们将其称为表观遗传可塑性。我们建议可塑性允许癌前或恶性细胞随机激活替代基因调控程序和/或经历非生理性细胞命运转变。一些随机变化将是无关紧要的“乘客”；其他人将授予健康并被选为“司机”。随着癌细胞分裂，获得性表观遗传状态可能通过 DNA 甲基化、抑制性染色质或基因调控回路的细胞分裂得以维持，从而产生促进恶性进展的适应性上克隆。我们强调了赋予表观遗传限制或可塑性的特定染色质畸变，并最终通过癌基因激活、肿瘤抑制基因沉默或适应性细胞命运转变来推动肿瘤进展。由确定的遗传刺激引发的畸变，例如染色质调节基因突变，尤其是关于机制的信息。例子包括促进染色质限制和阻碍分化的 Polycomb 抑制因子 EZH2 的功能获得性突变，以及破坏 DNA 甲基化平衡的代谢酶突变。后者导致的 DNA 甲基化变化与肿瘤抑制基因沉默有关，但也可能导致随机绝缘子破坏和癌基因激活。我们还仔细考虑了在没有遗传变化的情况下破坏染色质稳态的代谢和环境刺激。例子包括叶酸代谢和甲基化酶活性之间的联系、促进胃肠组织 DNA 高甲基化的环境因素，以及微环境压力对染色质调节器表达的潜在影响。纯粹的表观遗传机制可以解释很少或没有复发突变的肿瘤，以及缺乏遗传解释的肿瘤内异质功能表型。我们得出结论，染色质和表观遗传畸变可以赋予广泛的致癌特性，并可能满足癌症的所有特征。展望 表观遗传疗法的初步成功表明癌症表观遗传学具有重大临床影响的潜力。然而，实现这一承诺需要更清楚地了解肿瘤发生的表观遗传机制。越来越多的致癌表观遗传病变的识别为开发和测试其功能的概念和机制模型提供了机会。进展将需要新技术以单细胞精度探测染色质和表观遗传改变，以及忠实再现肿瘤表观遗传状态的实验模型。我们乐观地认为，对表观遗传可塑性和限制的更好理解可以推进评估肿瘤分期和异质性的诊断策略，并产生用于纠正表观遗传病变或利用表观遗传改变细胞的脆弱性的新治疗策略。表观遗传可塑性和癌症的标志。（左）正常染色质和相关的表观遗传机制稳定基因表达和细胞状态，同时促进对发育或环境线索的适当反应（蓝色细胞核代表正常细胞状态）。破坏染色质的遗传、环境和代谢损伤可导致染色质状态受到限制或过度放任。（中）过度宽松的染色质导致表观遗传可塑性；这种可塑性允许随机激活替代基因调控程序（红色细胞核代表癌症样细胞状态）。（右）一些随机变化将成为无关紧要的“乘客”，而其他随机变化将赋予健康并被选为“司机”；通过这种方式，染色质畸变有可能满足癌症的每个标志。染色质和相关的表观遗传机制稳定基因表达和细胞状态，同时也促进对发育或环境线索的适当反应。遗传、环境或代谢损伤会导致过度限制或过度放纵的表观遗传景观，从而导致癌症和其他疾病的发病机制。限制性染色质状态可能会阻止适当诱导肿瘤抑制程序或阻止分化。相比之下，宽容或“可塑性”状态可能允许随机癌基因激活或非生理性细胞命运转变。尽管许多随机事件将成为无关紧要的“乘客”，但有些随机事件会赋予细胞健康优势并被选为“驱动程序”。我们回顾了表观遗传畸变在肿瘤发生和进化中所发挥的广泛作用及其产生所有经典癌症标志的潜力。”有些人会赋予细胞健康优势，并被选为“驱动程序”。我们回顾了表观遗传畸变在肿瘤发生和进化中所发挥的广泛作用及其产生所有经典癌症标志的潜力。”有些人会赋予细胞健康优势，并被选为“驱动程序”。我们回顾了表观遗传畸变在肿瘤发生和进化中所发挥的广泛作用及其产生所有经典癌症标志的潜力。