Department of Biochemistry and Cellular Biology, National Center of Neurology and Psychiatry (NCNP), Tokyo 187-8502, Japan.
Institut Curie, PSL Research University, CNRS UMR, INSERM, Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Orsay 91400, France.
Dev Cell. 2024 Sep 9;59(17):2302-2319.e12. doi: 10.1016/j.devcel.2024.05.013. Epub 2024 Jun 3.
Normal cells coordinate proliferation and differentiation by precise tuning of gene expression based on the dynamic shifts of the epigenome throughout the developmental timeline. Although non-mutational epigenetic reprogramming is an emerging hallmark of cancer, the epigenomic shifts that occur during the transition from normal to malignant cells remain elusive. Here, we capture the epigenomic changes that occur during tumorigenesis in a prototypic embryonal brain tumor, medulloblastoma. By comparing the epigenomes of the different stages of transforming cells in mice, we identify nuclear factor I family of transcription factors, known to be cell fate determinants in development, as oncogenic regulators in the epigenomes of precancerous and cancerous cells. Furthermore, genetic and pharmacological inhibition of NFIB validated a crucial role of this transcription factor by disrupting the cancer epigenome in medulloblastoma. Thus, this study exemplifies how epigenomic changes contribute to tumorigenesis via non-mutational mechanisms involving developmental transcription factors.
正常细胞通过精确调节基因表达来协调增殖和分化，这种调节基于整个发育时间内表观基因组的动态变化。尽管非突变性表观遗传重编程是癌症的一个新兴标志，但正常细胞向恶性细胞转化过程中发生的表观基因组变化仍然难以捉摸。在这里，我们捕获了在典型的胚胎脑肿瘤——髓母细胞瘤中发生的肿瘤发生过程中的表观基因组变化。通过比较小鼠转化细胞的不同阶段的表观基因组，我们确定了转录因子核因子 I 家族，该家族已知是发育过程中细胞命运决定因素，是癌前和癌细胞表观基因组中的致癌调节因子。此外，NFIB 的遗传和药理学抑制通过破坏髓母细胞瘤中的癌症表观基因组，验证了该转录因子的关键作用。因此，这项研究说明了表观基因组变化如何通过涉及发育转录因子的非突变机制导致肿瘤发生。
