Chromatin interactions are essential in enhancer-promoter interactions (EPIs) and transcriptional regulation. CTCF and cohesin proteins located at chromatin interaction anchors and other DNA-binding proteins such as YY1, ZNF143, and SMARCA4 are involved in chromatin interactions. However, there is still no good overall understanding of proteins associated with chromatin interactions and insulator functions. Here, I describe a systematic and comprehensive approach for discovering DNA-binding motifs of transcription factors (TFs) that affect EPIs and gene expression. This analysis has identified 96 biased orientations [64 forward-reverse (FR) and 52 reverse-forward (RF)] of motifs that significantly affected the expression level of putative transcriptional target genes in monocytes, T cells, HMEC, and NPC and included CTCF, cohesin (RAD21 and SMC3), YY1, and ZNF143; as some TFs have more than one motif in databases, the total number (96) is smaller than the sum of FRs and RFs. KLF4, ERG, RFX, RFX2, HIF1, SP1, STAT3, and AP1 were associated with chromatin interactions. Many other TFs were also known to have chromatin-associated functions. A notable example is KLF4, which is associated with three-dimensional enhancer rewiring and transcriptional changes during the reprogramming of mouse embryonic fibroblasts to pluripotent stem cells. The transcription factor USF1 binds within the insulator at a site important in adjacent nucleosomes for generating histone modifications associated with active chromatin and, by inference, with barrier function. These findings contribute to the understanding of chromatin-associated motifs involved in transcriptional regulation, chromatin interactions/regulation, and histone modifications.
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