A computational approach for deciphering the interactions between proximal and distal gene regulators in GC B-cell response

Abstract

Abstract 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 present study aimed 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 for germinal center B cells, accompanied by dramatic rearrangements of the genome structure. We found that while the promoter-proximal regulatory 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 cofactors and proximal/distal transcription factors, which were co-expressed with their target genes. Some of these modules exhibited abnormal expression patterns in lymphoma. These findings suggest that the dysregulation of interactions between transcriptional and architectural factors is associated with chromatin reorganization failure, which may increase the risk of malignancy. Therefore, our computational approach helps decipher the transcriptional cis-regulatory code spatially interacting.