TReNCo: Topologically associating domain (TAD) aware regulatory network construction [version 1; peer review: 2 not approved]

Introduction: There has long been a desire to understand, describe, and model gene regulatory networks controlling numerous biologically meaningful processes like differentiation. Despite many notable improvements to models over the years, many models do not accurately capture subtle biological and chemical characteristics of the cell such as high-order chromatin domains of the chromosomes. Methods: Topologically Associated Domains (TAD) are one of these genomic regions that are enriched for contacts within themselves. Here we present TAD-aware Regulatory Network Construction or TReNCo, a memory-lean method utilizing epigenetic marks of enhancer and promoter activity, and gene expression to create context-specific transcription factor-gene regulatory networks. TReNCo utilizes common assays, ChIP-seq, RNA-seq, and TAD boundaries as a hard cutoff, instead of distance based, to efficiently create context-specific TF-gene regulatory networks. Results: We used TReNCo to define the enhancer landscape and identify transcription factors (TFs) that drive the cardiac development of the mouse. Conclusion: Our results show that we are able to build specialized adjacency regulatory network graphs containing biologically relevant connections and time dependent dynamics.