美国宾夕法尼亚大学Shelley L. Berger和M. Celeste Simon共同合作，近期取得重要工作进展。他们研究提出，核斑点能调节癌症的功能程序。相关研究成果2025年1月2日在线发表于《自然—细胞生物学》杂志上。

据介绍，核斑点是动态的核体，其特征是参与RNA产生的高浓度因子。尽管斑点的内容暗示了其在基因调控中的多方面作用，但它们的生物学功能尚不清楚。

研究人员探讨了人类癌症的斑点变化，发现了两个主要特征。一个斑点特征与健康的邻近组织相似，而另一个则不同，被认为是异常的癌症斑点状态。异常斑点显示细胞核内位置改变，TREX RNA输出复合物水平升高，并与透明细胞肾细胞癌（ccRCC）患者较差的预后相关，这是一种以HIF-1α转录因子过度激活为典型的癌症。

HIF-2α促进了某些靶基因与斑点的物理关联，这取决于本研究中定义的HIF-2α蛋白斑点靶向基序。研究人员在许多转录因子中鉴定出同源斑点靶向基序，表明DNA斑点靶向可能是一种通用的基因调控机制。通过整合功能、基因组和成像研究，研究人员发现HIF-2α基因调控程序受到斑点状态和废除HIF-2α驱动的斑点靶向的影响。

总之，这一研究表明，在ccRCC中，核斑点的一个关键生物学功能是调节特定HIF-2α调节靶基因的表达，进而影响患者的预后。除了ccRCC，肿瘤斑点状态与斑点相关基因区的功能途径和表达的改变广泛相关，揭示了人类癌症中核斑点与基因表达失调之间的普遍联系。

附：英文原文

Title: Nuclear speckles regulate functional programs in cancer

Author: Alexander, Katherine A., Yu, Ruofan, Skuli, Nicolas, Coffey, Nathan J., Nguyen, Son, Faunce, Christine L., Huang, Hua, Dardani, Ian P., Good, Austin L., Lim, Joan, Li, Catherine Y., Biddle, Nicholas, Joyce, Eric F., Raj, Arjun, Lee, Daniel, Keith, Brian, Simon, M. Celeste, Berger, Shelley L.

Issue&Volume: 2025-01-02

Abstract: Nuclear speckles are dynamic nuclear bodies characterized by high concentrations of factors involved in RNA production. Although the contents of speckles suggest multifaceted roles in gene regulation, their biological functions are unclear. Here we investigate speckle variation in human cancer, finding two main signatures. One speckle signature was similar to healthy adjacent tissues, whereas the other was dissimilar, and considered an aberrant cancer speckle state. Aberrant speckles show altered positioning within the nucleus, higher levels of the TREX RNA export complex and correlate with poorer patient outcomes in clear cell renal cell carcinoma (ccRCC), a cancer typified by hyperactivation of the HIF-2α transcription factor. We demonstrate that HIF-2α promotes physical association of certain target genes with speckles depending on HIF-2α protein speckle-targeting motifs, defined in this study. We identify homologous speckle-targeting motifs within many transcription factors, suggesting that DNA-speckle targeting may be a general gene regulatory mechanism. Integrating functional, genomic and imaging studies, we show that HIF-2α gene regulatory programs are impacted by speckle state and by abrogation of HIF-2α-driven speckle targeting. These findings suggest that, in ccRCC, a key biological function of nuclear speckles is to modulate expression of select HIF-2α-regulated target genes that, in turn, influence patient outcomes. Beyond ccRCC, tumour speckle states broadly correlate with altered functional pathways and expression of speckle-associated gene neighbourhoods, exposing a general link between nuclear speckles and gene expression dysregulation in human cancer.

DOI: 10.1038/s41556-024-01570-0

Source: https://www.nature.com/articles/s41556-024-01570-0