HNF1B-driven three-dimensional chromatin structure for molecular classification in pancreatic cancers

Area of Science:

• Genomics
• Cancer Biology
• Epigenetics

Background:

• Pancreatic cancer (PC) exhibits distinct molecular subtypes (classical/progenitor-like and basal/squamous-like) linked to clinical outcomes.
• Transcription factors (TFs) are implicated in these subtypes, but the underlying mechanisms remain unclear.
• Epigenetic regulation and chromatin structure dynamics are crucial for establishing transcriptional profiles.

Purpose of the Study:

• To investigate the relationship between three-dimensional (3D) genome organization and molecular subtypes in human pancreatic cancer.
• To elucidate the role of specific transcription factors, such as HNF1B, in modulating 3D genome structure and gene expression in PC.

Main Methods:

• Hi-C analysis was employed to map genome-wide 3D interactions.
• Computational analysis of 3D genome architecture, including compartments, topologically associating domains (TADs), and enhancer-promoter loops.
• Functional experiments involving forced expression of HNF1B in PC organoids.

Main Results:

• Specific 3D genome elements (compartments, TADs, loops) correlated with gene expression patterns in PC subtypes.
• Forced expression of HNF1B in squamous-type PC organoids altered gene expression consistent with progenitor and squamous subtypes.
• HNF1B-induced genomic changes involved compartment modulation, H3K27ac redistribution, and required an intrinsically disordered region, suggesting phase separation involvement.

Conclusions:

• 3D genome structure plays a significant role in defining pancreatic cancer molecular subtypes.
• The transcription factor HNF1B can remodel 3D genome architecture and influence subtype-specific gene expression.
• Mapping TF-induced 3D structural changes offers a valuable approach for understanding PC molecular heterogeneity.