STAG2 regulates interferon signaling in melanoma via enhancer loop reprogramming

Area of Science:

• Genomics
• Cancer Biology
• Epigenetics

Background:

• The cohesin complex organizes 3D genome structure via DNA loops.
• Stromal antigen 2 (STAG2), a cohesin subunit, is frequently mutated in cancers.
• The role of STAG2 inactivation in 3D genome organization and gene expression in cancer is unclear.

Purpose of the Study:

• To investigate the impact of STAG2 inactivation on 3D genome organization and gene expression in melanoma.
• To identify direct targets of STAG2 and understand its regulatory mechanisms in cancer.

Main Methods:

• Depletion of STAG2 in melanoma cells.
• RNA-sequencing (RNA-seq).
• STAG2 Chromatin Immunoprecipitation sequencing (ChIP-seq).
• Histone H3 lysine 27 acetylation (H3K27ac) High-throughput Chromatin Interaction analysis by paired-end tag sequencing (HiChIP).

Main Results:

• STAG2 depletion caused topologically associating domain (TAD) expansion and altered DNA loop formation, involving a switch to STAG1.
• Interferon Regulatory Factor 9 (IRF9) was identified as a direct target of STAG2.
• Loss of STAG2 activated IRF9, enhancing type I interferon signaling and PD-L1 expression.

Conclusions:

• STAG2 inactivation impacts 3D genome organization through a STAG2-STAG1 switch.
• STAG2 loss-mediated IRF9 activation influences interferon signaling and PD-L1 expression in melanoma.
• These findings reveal a link between STAG2 function, 3D genome regulation, and immune evasion in STAG2-mutant cancers.