NELFE的相分离调节染色质可及性以促进肝细胞癌中的二分信号通路。

Phase separation of NELFE modulates chromatin accessibility to promote dichotomous signaling pathways in hepatocellular carcinoma.

作者信息

Dang Hien, Lucci Alvaro, Barry Anna, Johnson Victoria, Ruiz Brittany, Reynolds Laura, Wojnar Adam, Chewe Kasonde, Pomyen Yotsawat, Eckert Christoph, Zhang Kai, Hill Jason, Shah Ashesh, Bodzin Adam, Grabocka Elda, Gaida Matthias, Fawzi Nicolas

机构信息

Thomas Jefferson University.

Brown University.

出版信息

Res Sq. 2025 Apr 25:rs.3.rs-5843408. doi: 10.21203/rs.3.rs-5843408/v1.

DOI:10.21203/rs.3.rs-5843408/v1

PMID:40313774

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12045374/

Abstract

Biomolecular condensates partition various cellular processes including transcription, DNA repair, and RNA metabolism. We report NELFE, a member of the Negative Elongation Factor complex required for Polymerase II (Pol II) pausing, forms distinct foci mediated by two low complexity sequences. We show NELFE is oncogenic in hepatocellular carcinoma (HCC) by undergoing liquid-liquid phase separation (LLPS) with SMARCB1 to modulate chromatin accessibility to downregulate pro-apoptotic genes through Pol II pausing while activating pro-growth signals to promote HCC progression. Our work highlights the importance of NELFE LLPS as a mechanism of chromatin accessibility to regulate both paused and non-paused genes to drive tumorigenesis in hepatocellular carcinoma.

摘要

生物分子凝聚体分隔了包括转录、DNA修复和RNA代谢在内的各种细胞过程。我们报告称，负向延伸因子复合物（Negative Elongation Factor complex）的成员NELFE是聚合酶II（Pol II）暂停所必需的，它由两个低复杂性序列介导形成不同的焦点。我们发现，在肝细胞癌（HCC）中，NELFE通过与SMARCB1进行液-液相分离（LLPS）而具有致癌性，从而调节染色质可及性，通过Pol II暂停下调促凋亡基因，同时激活促生长信号以促进HCC进展。我们的工作突出了NELFE液-液相分离作为一种染色质可及性机制的重要性，该机制可调节暂停和非暂停基因，从而驱动肝细胞癌的肿瘤发生。