Cancer-Specific Retargeting of BAF Complexes by a Prion-like Domain

Abstract

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.

Protein Phase Separation: A New Phase in Cell Biology

“…Indeed, the transcriptional activation potential of FUS LCD, as well as its human homologs EWSR1 and TAF15, implicated together in a family of cancers, is highly correlated with their in vitro hydrogel binding capability and ability to recruit the C-terminal domain of polymerase II to such hydrogels [90]. The mechanism through which FUS LCD and its homologs mediate transcriptional activation remains unclear, but is thought to involve phase separation [5,10,121,122]. Additionally, increased SG and paraspeckle formation have been linked to a poor prognosis for cancer survival [123–125].…”

“…These questions are starting to be answered, and recent advances in interdisciplinary approaches have fueled the emergence of insights into their organization, molecular properties, and regulation [2–4]. A growing understanding of the underlying molecular principles and the physicochemical forces that drive the formation of membraneless organelles (see Glossary) has enabled the elucidation of their diverse functions in a variety of cellular processes, including the stress response, the regulation of gene expression, and the control of signal transduction [5–8]. In the past few years, there has been increasing evidence for the involvement of membraneless organelles in age-related disorders, such as amyotrophic lateral sclerosis (ALS) [9–16].…”

Prion-like Domains Program Ewing’s Sarcoma

“…In this issue of Cell , ground-breaking studies by Rivera, Kadoch, and colleagues demonstrate that the PrLD of the EWS-FLI1 fusion protein phase separates and recruits BAF (BRG1/BRM-associated factor, also known as SWI/SNF) chromatin-remodeling complexes to tumor-specific enhancers, thereby activating the transcriptional events of Ewing’s sarcoma. These findings establish that translocated PrLDs can elicit phase-separation events, which unleash aberrant transcriptional cascades that cause cancer (Boulay et al, 2017). …”

“…Using an unbiased mass-spectrometry approach, Boulay et al establish that BAF complexes interact transiently with EWSR1 in a variety of cell types and also with EWS-FLI1 in Ewing’s sarcoma (Boulay et al, 2017). EWS-FLI1 acts as a pioneer factor in mesenchymal stem cells, the probable cell of origin for Ewing’s sarcoma (Riggi et al, 2014).…”

“…Thus, an emergent property provided by the translocated PrLD enables EWS-FLI1 pioneer activity. Moreover, EWS-FLI1 forms numerous nuclear foci, whereas FLI1 remains diffuse (Boulay et al, 2017). Thus, the ability of the PrLD in EWS-FLI1 to phase separate likely enables pioneer activity and recruitment of EWSR1 and BAF complexes to GGAA microsatellite repeats.…”