A computational approach for deciphering the interactions between proximal and distal regulators in B cell differentiation

Delineating the intricate interplay between promoter-proximal and -distal regulators is crucial for understanding the function of transcriptional mediator complexes implicated in the regulation of gene expression. The aim of the present study was to develop a computational method for accurately modeling the spatial proximal and distal regulatory interactions. Our method combined regression-based models to identify key regulators through gene expression prediction and a graph- embedding approach to detect coregulated genes. This approach enabled a detailed investigation of the gene regulatory mechanisms underlying peripheral B cell differentiation, accompanied by dramatic rearrangements of the genome structure. We found that while the promoter-proximal elements were the principal regulators of gene expression, the distal regulators fine-tuned transcription. Moreover, our approach unveiled the presence of modular regulators, such as structural cofactors and proximal/distal transcriptional factors, which were co-expressed with their target genes. These findings imply that the dysregulation of interactions between transcriptional and structural factors is associated with chromatin reorganization failure and ultimately an increased risk of malignancy. We envisage that our computational approach will help crack the transcriptional cis-regulatory code of the three-dimensional network regulating gene expression.