Long-Range Chromatin Interactions Drive Mutant TERT Promoter Activation

Area of Science:

• * Molecular biology
• * Cancer genetics
• * Epigenetics

Background:

• * Cancer-specific mutations in the TERT promoter are linked to TERT gene reactivation.
• * Understanding the mechanism of TERT reactivation is crucial for developing targeted cancer therapeutics.
• * The TERT gene plays a key role in maintaining telomere length, contributing to cancer cell immortality.

Purpose of the Study:

• * To elucidate the mechanism by which cancer-specific TERT promoter mutations drive TERT gene reactivation.
• * To identify the role of transcription factor GABPA in mediating TERT reactivation.
• * To explore the potential of targeting this mechanism for cancer therapy.

Main Methods:

• * Investigated TERT promoter mutations (-146C>T and -124C>T) and their effect on TERT transcription.
• * Utilized CRISPR technology to reverse mutations and delete interacting chromatin regions.
• * Analyzed GABPA binding, chromatin interactions, histone modifications, and POL2 recruitment.

Main Results:

• * GABPA specifically binds to mutant TERT promoters, mediating long-range chromatin interactions and active histone marks.
• * CRISPR-mediated correction of mutations or deletion of interacting chromatin abrogates GABPA binding and suppresses TERT transcription.
• * Introduction of TERT promoter mutations induces GABPA binding, leading to TERT upregulation via chromatin interactions and histone modifications.

Conclusions:

• * GABPA recruitment to mutant TERT promoters is a key driver of TERT reactivation in cancer.
• * This cancer-specific mechanism provides a potential therapeutic target for inhibiting telomerase.
• * Targeting this pathway could lead to novel treatments for a wide range of human cancers.