Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Cell Stem Cell. 2010 Jun 4;6(6):591-602. doi: 10.1016/j.stem.2010.03.016.
Wilms tumor is the most common pediatric kidney cancer. To identify transcriptional and epigenetic mechanisms that drive this disease, we compared genome-wide chromatin profiles of Wilms tumors, embryonic stem cells (ESCs), and normal kidney. Wilms tumors prominently exhibit large active chromatin domains previously observed in ESCs. In the cancer, these domains frequently correspond to genes that are critical for kidney development and expressed in the renal stem cell compartment. Wilms cells also express "embryonic" chromatin regulators and maintain stem cell-like p16 silencing. Finally, Wilms and ESCs both exhibit "bivalent" chromatin modifications at silent promoters that may be poised for activation. In Wilms tumor, bivalent promoters correlate to genes expressed in specific kidney compartments and point to a kidney-specific differentiation program arrested at an early-progenitor stage. We suggest that Wilms cells share a transcriptional and epigenetic landscape with a normal renal stem cell, which is inherently susceptible to transformation and may represent a cell of origin for this disease.
威尔姆斯瘤是最常见的儿童肾部癌症。为了鉴定驱动这种疾病的转录和表观遗传机制，我们比较了威尔姆斯瘤、胚胎干细胞 (ESC) 和正常肾脏的全基因组染色质图谱。威尔姆斯瘤显著表现出先前在 ESC 中观察到的大的活性染色质域。在癌症中，这些结构域通常对应于对肾脏发育至关重要且在肾干细胞区室中表达的基因。威尔姆斯细胞还表达“胚胎”染色质调节因子，并维持类似于干细胞的 p16 沉默。最后，威尔姆斯瘤和 ESC 都在沉默启动子处表现出“双价”染色质修饰，可能处于激活准备状态。在威尔姆斯瘤中，双价启动子与在特定肾区室中表达的基因相关，表明该疾病处于早期祖细胞阶段的肾脏特异性分化程序被阻断。我们认为，威尔姆斯细胞与正常肾干细胞具有相似的转录和表观遗传特征，这使其易受转化影响，并且可能是该疾病的起源细胞。
