Oncogenic Notch Promotes Long-Range Regulatory Interactions within Hyperconnected 3D Cliques.

Area of Science:

• Genomics
• Cancer Biology
• Epigenetics

Background:

• Chromatin loops facilitate enhancer-promoter interactions for gene regulation.
• The role of oncogenic transcription factors, like Notch, in cancer genome 3D organization is poorly understood.

Purpose of the Study:

• To investigate how oncogenic Notch signaling affects the 3D genome organization in cancer.
• To identify novel regulatory mechanisms involving chromatin looping and spatial clustering of regulatory elements.

Main Methods:

• Genome-wide chromatin looping analysis in triple-negative breast cancer and B cell lymphoma.
• Loss- and gain-of-function experiments to assess Notch's regulatory roles.

Main Results:

• Notch signaling instructs enhancer repositioning, altering target gene regulation.
• Notch-instructed loops form spatial clusters called "3D cliques."
• Notch preferentially targets hyperconnected 3D cliques regulating proto-oncogenes.

Conclusions:

• Oncogenic Notch signaling dysregulates transcription via widespread changes in 3D genome organization.
• The formation and targeting of 3D cliques represent a novel mechanism of oncogenic transcription factor activity.