64 / 2026-04-03 17:38:19

FOXA1 Orchestrates 3D Genome Folding via Targeted NIPBL Recruitment

3D genome,Loop Extrusion,Prostate Cancer,Pioneer Factor

Despite the well-established role of pioneer factors in epigenetic reprogramming, the interplay between these factors and the spatial organization of the genome has yet to be fully characterized. This study identifies the pioneer transcription factor FOXA1 as a master regulator of 3D genome architecture by mediating the recruitment of NIPBL, the cohesin loading factor, to chromatin. While cohesin-mediated loop extrusion organizes the genome, the mechanisms defining its entry sites have remained elusive.

Key Findings:

Targeted Loop Extrusion: FOXA1 directs NIPBL specifically to intra-topologically associating domain (intra-TAD) regions. This localization facilitates symmetric loop extrusion, maintaining the structural connectivity within genomic domains.

Hierarchical Control: Rapid depletion of FOXA1 disrupts NIPBL binding and selectively impairs intra-TAD loops. This establishes FOXA1 as a primary determinant in the hierarchical folding of genome.

Oncogenic Reprogramming: A recurrent FOXA1 mutation (R219S) found in prostate cancer alters its DNA-binding specificity. This mutation redirects the FOXA1-NIPBL complex from intra-TAD regions to TAD boundaries by recognizing non-canonical motifs.

Functional Impact: This FOXA1-driven redistribution fosters a more insulated and "tumor-aggressive" genome, demonstrating how a single point mutation in a pioneer factor can rewire the physical landscape of the nucleus to promote cancer progression.