PO.MCB07.01 · 分子与细胞生物学
NELFE和SMARCB1协同调控染色质可及性并使肝细胞癌中MYC驱动的基因激活成为可能
NELFE and SMARCB1 cooperate to regulate chromatin accessibility and allow MYC-driven gene activation in hepatocellular carcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
肝癌在美国是一个严重且日益加剧的问题，自1980年以来病例数增加了两倍多。尽管在诊断和治疗方面取得了一些进展，但五年生存率仍低于20%。肝细胞癌（HCC）是最常见的肝癌类型，通常涉及MYC基因的异常激活，这有助于癌细胞的生长和存活。遗憾的是，MYC很难用药物直接靶向。因此，研究人员对了解控制或支持MYC活性的蛋白质很感兴趣。其中一种蛋白质是NELFE，它通过调控基因的开启和关闭方式来调控基因表达。我们认为NELFE很重要，因为它帮助MYC接近并激活其靶基因，从而促进癌症生长。为研究这一点，我们使用CRISPR/Cas9从肝癌细胞中去除NELFE，并进行了ATAC-seq和ChIP-seq实验，以观察这如何影响MYC和DNA的结构。我们发现，在没有NELFE的情况下，DNA变得可及性降低，MYC在重要基因附近结合的能力减弱。然而，NELFE并不直接结合这些MYC位点，表明它与另一种蛋白质协同发挥作用。对NELFE进行的质谱分析鉴定出SWI/SNF染色质重塑复合物的组分SMARCB1为一个主要的相互作用伙伴，它将NELFE与MYC联系起来。尽管SMARCB1在许多癌症中被广泛认为是一种肿瘤抑制因子，但在我们的肝癌系统中，它似乎起到致癌基因的作用，促进癌症生长。我们还表明，NELFE和SMARCB1在细胞中形成特殊的相分离结构，帮助组织DNA，影响暂停型（paused）和非暂停型基因。这些结构使染色质保持开放，使MYC更加活跃并与其靶基因相互作用。此外，当NELFE缺失时，SMARCB1和MYC无法正常相互作用，导致MYC介导的基因激活减少。总之，NELFE通过与SMARCB1协同作用改变DNA的组织方式，从而帮助MYC促进肝癌。理解这一关系可能带来针对依赖MYC的肝癌的新疗法。
查看英文原文 English abstract
Liver cancer is a serious and growing problem in the United States, with cases having more than tripled since 1980. Although there have been some advances in diagnosis and treatment, the five-year survival rate remains below 20%. Hepatocellular carcinoma (HCC), the most common type of liver cancer, often involves aberrant activation of the MYC gene, which helps cancer cells grow and survive. Unfortunately, MYC is very difficult to target directly with drugs. As such, researchers are interested in understanding proteins that control or support MYC's activity. One such protein is NELFE, which regulates gene expression by regulating how genes are turned on and off. We believe NELFE is important because it helps MYC access and activate its target genes, promoting cancer growth. To study this, we used CRISPR/Cas9 to remove NELFE from liver cancer cells and performed ATAC-seq and ChIP-seq experiments to see how this affected MYC and the structure of DNA. We found that without NELFE, the DNA became less accessible, and MYC was less able to bind near important genes. However, NELFE does not directly bind to these MYC sites, suggesting it works together with another protein. Mass spectrometry of NELFE identified SMARCB1, a component of the SWI/SNF chromatin remodeling complex, as a major interacting partner that links NELFE to MYC. Although SMARCB1 is widely known as a tumor suppressor in many cancers, in our liver cancer system, it appears to act as an oncogene, promoting cancer growth. We also showed that NELFE and SMARCB1 form special phase-separated structures in cells that help organize DNA, influencing both paused and non-paused genes. These structures keep the chromatin open, allowing MYC to be more active and interact with its target genes. Moreover, when NELFE is missing, SMARCB1 and MYC cannot interact properly, leading to reduced gene activation by MYC. In summary, NELFE helps MYC promote liver cancer by working with SMARCB1 to change how DNA is organized. Understanding this relationship could lead to new treatments for liver cancers that depend on MYC.
利益披露 Disclosure
A. Lucci, None..
A. E. Barry, None..
L. M. Reynolds, None..
B. N. Ruiz, None..
T. Nguyen, None..
P. Choochuen, None..
K. Zhang, None..
H. T. Dang, None.