Inter3D: Capture of TAD Reorganization Endows Variant Patterns of Gene Transcription

Topologically associating domain (TAD) reorganization commonly occurs in the cell nucleus and contributes to gene activation and inhibition through the separation or fusion of adjacent TADs. However, identification of functional genes impacted by TAD alteration and the mechanism of TAD reorganization underlying gene transcription remain to be fully elucidated. Here, we first developed a novel approach termed Inter3D to specifically identify genes regulated by TAD reorganization. Our study revealed that the segregation of TADs led to the disruption of intrachromosomal looping at the myosin light chain 12B (MYL12B) locus, via the meticulous reorganization of TADs mediating epigenomic landscapes within tumor cells, thereby exhibiting a significant correlation with the downregulation of its transcriptional activity. Conversely, the fusion of TADs facilitated intrachromosomal interactions, suggesting a potential association with the activation of cytochrome P450 family 27 subfamily B member 1 (CYP27B1). Our study provides comprehensive insight into the capture of TAD rearrangement-mediated gene loci and moves toward understanding the functional role of TAD reorganization in gene transcription. The Inter3D pipeline used in this study is freely available at https://github.com/bm2-lab/inter3D.