Structural variation cooperates with permissive chromatin to control enhancer hijacking-mediated oncogenic...

Area of Science:

• Genomics
• Cancer Biology
• Epigenetics

Background:

• Structural variants (SVs) can activate oncogenes in cancer through enhancer hijacking, but the underlying mechanisms are unclear.
• Understanding SVs' impact on gene regulation and chromatin is crucial for cancer research.

Purpose of the Study:

• To develop a multimodal approach for analyzing SVs' effects on gene regulation and chromatin in leukemia.
• To investigate the molecular determinants of enhancer hijacking-mediated oncogene activation.

Main Methods:

• Integrated analysis of genome sequencing, chromosome conformation, chromatin state, and transcriptomic data.
• CRISPR engineering of patient-derived leukemia cells.
• Quantitative analysis of transcriptional and structural changes.

Main Results:

• Identified pathogenic SVs, including t(5;14) translocations, causing BCL11B enhancer hijacking and TLX3 activation in pediatric leukemia.
• Demonstrated that epigenetic perturbation of hijacked enhancers impairs TLX3 transcription, essential for leukemia cell growth.
• Uncovered a mechanism where SV-induced enhancer hijacking depends on reduced DNA hypermethylation at the TLX3 promoter.

Conclusions:

• Cooperation between genetic alterations and permissive chromatin drives SV-mediated oncogene activation.
• Findings have implications for understanding gene transcription after epigenetic therapies in leukemia.
• Interplay between genetic and chromatin variations offers new therapeutic intervention strategies.