Transcription factors organize into functional groups on the linear genome and in 3D chromatin

• Published in: Heliyon Vol. 9; no. 8; p. e18211
• Main Authors: Vadnala, Rakesh Netha, Hannenhalli, Sridhar, Narlikar, Leelavati, Siddharthan, Rahul
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2023; Elsevier
• Subjects: Chromatin; Transcription factors; Chromatin; Transcription factors
• ISSN: 2405-8440; 2405-8440
• DOI: 10.1016/j.heliyon.2023.e18211

Transcription factors (TFs) and their binding sites have evolved to interact cooperatively or competitively with each other. Here we examine in detail, across multiple cell lines, such cooperation or competition among TFs both in sequential and spatial proximity (using chromatin conformation capture assays), considering in vivo binding data as well as TF binding motifs in DNA. We ascertain significantly co-occurring (“attractive”) or avoiding (“repulsive”) TF pairs using robust randomized models that retain the essential characteristics of the experimental data. Across human cell lines TFs organize into two groups, with intra-group attraction and inter-group repulsion. This is true for both sequential and spatial proximity, and for both in vivo binding and sequence motifs. Attractive TF pairs exhibit significantly more physical interactions suggesting an underlying mechanism. The two TF groups differ significantly in their genomic and network properties, as well in their function—while one group regulates housekeeping function, the other potentially regulates lineage-specific functions, that are disrupted in cancer. Weaker binding sites tend to occur in spatially interacting regions of the genome. Our results suggest that a complex pattern of spatial cooperativity of TFs and chromatin has evolved with the genome to support housekeeping and lineage-specific functions. •We present a method for learning significantly co-occurring pairs of TFs from high-throughput experiments.•TFs associate in two groups, differing in protein-protein interactions, protein-DNA binding, and biological function.•One group tends to bind proximally to genes, and is conserved in function across cell-types.•The other tends to bind distally, and its function is more specific to cell lineage.•Cooperativity among TFs appears modulated by 3D chromatin architecture as well as TF affinity to specific DNA binding sites.