Abstract
Low-complexity domains (LCD) in transcription factors can form high-concentration interaction hubs.
Major finding: Low-complexity domains (LCD) in transcription factors can form high-concentration interaction hubs.
Concept: Transcription factor LCD hubs stabilize DNA binding and recruit RNA Pol II to activate transcription.
Impact: Rapid, reversible LCD–LCD interactions may represent a fundamental mechanism of transcriptional control.
Although many transcription factors have well-structured DNA binding domains, their transactivation domains often harbor low-complexity sequence domains (LCD) that adopt an intrinsically disordered conformation, hampering conventional structural determination and pharmacologic targeting. Mutations in transcription factor LCDs have been implicated in transcriptional disruption and cancer. However, it is unclear how transcription factor LCDs drive transactivation. Chong and colleagues used high-resolution imaging strategies to characterize the dynamic behavior of transcription factor LCDs at target genomic loci under physiologic conditions. Integrating a synthetic Lac operator array into cells that express various tagged transcription factor LCDs fused to LacI resulted in LacO array recruitment of a large number of LCD–LacI molecules via targeted DNA binding, forming concentrated local LCD interaction hubs in the nucleus. Further, LCD–LCD interactions could occur even without binding to DNA, indicating the ability of LCD hubs to self-assemble. LCD–LCD interactions stabilized transcription factor binding to DNA, and LCD hubs could interact with RNA polymerase II (Pol II), a key step in transactivation. The LCD–LCD interactions were sequence-specific, highly dynamic, and reversible, and could be disrupted by 1,6-hexanediol, a chemical that dissolves various intracellular membrane-less compartments. Although LCD–LCD interactions could form independent of DNA, transcription factor–DNA interactions maintained a high local concentration of transcription factor LCDs, stabilizing both LCD–LCD interactions and transcription factor–DNA interactions. EWS–FLI1, a fusion protein that drives Ewing sarcoma tumorigenesis, harbors an LCD and binds to GGAA microsatellites in the human genome. The EWS LCD–LCD interactions facilitated formation of EWS–FLI1 hubs at GGAA microsatellite DNA elements in Ewing sarcoma cells, and were required for the EWS–FLI1-mediated transcriptional activation to drive oncogenic gene expression. Although liquid–liquid phase separation was detected with gross overexpression of LCDs, it was not detected for the functional EWS LCD interaction hubs formed at native genomic loci in the presence of endogenous EWS–FLI1. Collectively, these findings reveal a mechanism by which transcription factor LCDs may drive transcription.
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