Boulay Gaylor, Sandoval Gabriel J, Riggi Nicolo, Iyer Sowmya, Buisson Rémi, Naigles Beverly, Awad Mary E, Rengarajan Shruthi, Volorio Angela, McBride Matthew J, Broye Liliane C, Zou Lee, Stamenkovic Ivan, Kadoch Cigall, Rivera Miguel N
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Cell. 2017 Sep 21;171(1):163-178.e19. doi: 10.1016/j.cell.2017.07.036. Epub 2017 Aug 24.
Alterations in transcriptional regulators can orchestrate oncogenic gene expression programs in cancer. Here, we show that the BRG1/BRM-associated factor (BAF) chromatin remodeling complex, which is mutated in over 20% of human tumors, interacts with EWSR1, a member of a family of proteins with prion-like domains (PrLD) that are frequent partners in oncogenic fusions with transcription factors. In Ewing sarcoma, we find that the BAF complex is recruited by the EWS-FLI1 fusion protein to tumor-specific enhancers and contributes to target gene activation. This process is a neomorphic property of EWS-FLI1 compared to wild-type FLI1 and depends on tyrosine residues that are necessary for phase transitions of the EWSR1 prion-like domain. Furthermore, fusion of short fragments of EWSR1 to FLI1 is sufficient to recapitulate BAF complex retargeting and EWS-FLI1 activities. Our studies thus demonstrate that the physical properties of prion-like domains can retarget critical chromatin regulatory complexes to establish and maintain oncogenic gene expression programs.
转录调节因子的改变可在癌症中协调致癌基因表达程序。在此，我们表明，在超过20%的人类肿瘤中发生突变的BRG1/BRM相关因子（BAF）染色质重塑复合体，与EWSR1相互作用，EWSR1是一类具有朊病毒样结构域（PrLD）的蛋白质家族成员，这些蛋白质在与转录因子的致癌融合中经常作为伙伴。在尤因肉瘤中，我们发现BAF复合体被EWS-FLI1融合蛋白招募到肿瘤特异性增强子，并促进靶基因激活。与野生型FLI1相比，这一过程是EWS-FLI1的一种新功能特性，并且依赖于EWSR1朊病毒样结构域相变所必需的酪氨酸残基。此外，将EWSR1的短片段与FLI1融合足以重现BAF复合体的重新靶向和EWS-FLI1活性。因此，我们的研究表明，朊病毒样结构域的物理特性可以重新靶向关键的染色质调节复合体，以建立和维持致癌基因表达程序。
