1Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3000 Australia.
11Present Address: Josep Carreras Leukaemia Research Institute, Barcelona, 08021 Spain.
Commun Biol. 2019 Jan 28;2:39. doi: 10.1038/s42003-019-0284-y. eCollection 2019.
The three-dimensional organization of the genome contributes to its maintenance and regulation. While chromosomal regions associate with nucleolar ribosomal RNA genes (rDNA), the biological significance of rDNA-genome interactions and whether they are dynamically regulated during disease remain unclear. rDNA chromatin exists in multiple inactive and active states and their transition is regulated by the RNA polymerase I transcription factor UBTF. Here, using a MYC-driven lymphoma model, we demonstrate that during malignant progression the rDNA chromatin converts to the open state, which is required for tumor cell survival. Moreover, this rDNA transition co-occurs with a reorganization of rDNA-genome contacts which correlate with gene expression changes at associated loci, impacting gene ontologies including B-cell differentiation, cell growth and metabolism. We propose that UBTF-mediated conversion to open rDNA chromatin during malignant transformation contributes to the regulation of specific gene pathways that regulate growth and differentiation through reformed long-range physical interactions with the rDNA.
基因组的三维组织有助于其维持和调节。虽然染色体区域与核仁核糖体 RNA 基因（rDNA）相关，但 rDNA-基因组相互作用的生物学意义以及它们在疾病过程中是否被动态调节仍不清楚。rDNA 染色质存在于多种非活性和活性状态，其转变受 RNA 聚合酶 I 转录因子 UBTF 调节。在这里，我们使用 MYC 驱动的淋巴瘤模型表明，在恶性进展过程中，rDNA 染色质转换为开放状态，这是肿瘤细胞存活所必需的。此外，这种 rDNA 转变与 rDNA-基因组接触的重新组织同时发生，与相关基因座的基因表达变化相关，影响基因本体论，包括 B 细胞分化、细胞生长和代谢。我们提出，恶性转化过程中 UBTF 介导的 rDNA 染色质向开放状态的转化有助于调节特定基因途径，这些基因途径通过与 rDNA 的重新形成的长距离物理相互作用来调节生长和分化。
