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依赖trim28的发育异质性通过不同的表观遗传状态决定癌症易感性

原文发布日期：2025-01-24

英文摘要：

摘要翻译：

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依赖trim28的发育异质性通过不同的表观遗传状态决定癌症易感性

TRIM28-dependent developmental heterogeneity determines cancer susceptibility through distinct epigenetic states

原文发布日期：2025-01-24

英文摘要：

Mutations in cancer risk genes increase susceptibility, but not all carriers develop cancer. Indeed, while DNA mutations are necessary drivers of cancer, only a small subset of mutated cells go on to cause the disease. To date, the mechanisms underlying individual cancer susceptibility remain unclear. Here, we took advantage of a unique mouse model of intrinsic developmental heterogeneity (Trim28+/D9) to investigate whether early-life epigenetic variation influences cancer susceptibility later in life. We found that heterozygosity of Trim28 is sufficient to generate two distinct early-life epigenetic states associated with differing cancer susceptibility. These developmentally primed states exhibit differential methylation patterns at typically silenced heterochromatin, detectable as early as 10 days of age. The differentially methylated loci are enriched for genes with known oncogenic potential, frequently mutated in human cancers and correlated with poor prognosis. This study provides genetic evidence that intrinsic developmental heterogeneity can prime individual, lifelong cancer susceptibility.

摘要翻译：

癌症易发基因的突变会增加患癌风险，但并非所有携带突变的人终将患病。实际上，DNA突变是癌症发生的必要因素，然而只有少数突变后的细胞会引发疾病。截至目前，个体癌症易发性的机制仍不明确。在此研究中，我们利用了独特的TRIM28+/D9小鼠模型（基于内在发育异质性）来探讨早期环境因素是否影响寿命 later-life的癌症易发性。我们发现，TRIM28的杂合状态足以产生两种具有不同癌症易发性的早期表观遗传态。这些由发育阶段决定的表观遗传状态在通常沉默的染色体 silenced区表现出不同的甲基化模式，在出生10天时即可检测到。甲基化位点中，差异性区域富集了与已知癌基因潜在功能相关、人类癌症中常被突变的基因以及与 poor prognosis 相关的基因。这项研究提供了一种遗传证据，表明内在发育异质性可以为个体带来一生的癌症易发性。