Chromatin profiling reveals relocalization of lysine-specific demethylase 1 by an oncogenic fusion protein

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• Paediatric cancers often have simple mutational landscapes driven by single events.
• Ewing sarcoma is driven by the EWS/FLI fusion protein, a transcription factor causing widespread gene dysregulation.
• Lysine-specific demethylase 1 (LSD1) is a functional partner of EWS/FLI, but its role in fusion-directed epigenomic regulation is unclear.

Purpose of the Study:

• To investigate the role of LSD1 in EWS/FLI-driven epigenomic regulation and gene activation in Ewing sarcoma.
• To understand how LSD1 participates in the aberrant gene activation characteristic of this paediatric cancer.

Main Methods:

• Investigated the dynamic rearrangement of LSD1 in response to EWS/FLI.
• Examined the colocalization of LSD1 with EWS/FLI binding sites genome-wide.
• Assessed the role of LSD1 in the formation of Ewing sarcoma super-enhancers.

Main Results:

• EWS/FLI causes dynamic changes in LSD1 distribution across the genome.
• LSD1 colocalizes with EWS/FLI at its binding sites, indicating a role in gene activation.
• LSD1 is crucial for establishing Ewing sarcoma super-enhancers at specific microsatellite regions.

Conclusions:

• EWS/FLI significantly alters LSD1 distribution, impacting the enhancer landscape in Ewing sarcoma.
• LSD1 plays a key role in mediating EWS/FLI's transcriptional activity and driving malignancy.
• Targeting the LSD1-EWS/FLI interaction may offer a therapeutic strategy for Ewing sarcoma.