No abstract

Transcription factors (TFs) are proteins that affect gene expression by binding to regulatory regions of DNA in a sequence specific manner. The binding of TFs to DNA is controlled by many factors, including the DNA sequence, concentration of TF, chromatin accessibility and co-factors. Here, we systematically investigated the binding mechanism of hundreds of TFs by analysing ChIP-seq data with our explainable statistical model, ChIPanalyser. This tool uses as inputs the DNA sequence binding motif; the capacity to distinguish between strong and weak binding sites; the concentration of TF; and chromatin accessibility. We found that approximately one third of TFs are predicted to bind the genome in a DNA accessibility independent fashion, which includes TFs that can open the chromatin, their co-factors and TFs with similar motifs. Our model predicted this to be the case when the TF binds to its strongest binding regions in the genome, and only a small number of TFs have the capacity to bind dense chromatin at their weakest binding regions, such as CTCF, USF2 and CEBPB. Our study demonstrated that the binding of hundreds of human and mouse TFs is predicted by ChIPanalyser with high accuracy and showed that many TFs can bind dense chromatin.

Cumulative evidence suggests that somatosensorial stimulation through exposure to enriched environments improves homeostasis and enhances central nervous system functions. Immune system functions are also modulated by exposure to enriched environments, which enhance phagocytosis and chemotaxis while attenuating the inflammatory response induced by lipopolysaccharide exposure or hypercaloric diets. Consistent with these, here we show that exposure to an enriched environment attenuates inflammation in the colon in two colitis experimental models. Exposing animals to an enriched environment reduced weight loss, colon length shortening, and decreased disease activity index after dextran sodium sulfate or trinitrobenzene sulfonic acid treatment, compared with animals housed in a normal environment. Histologically, after colitis induction, exposure to an enriched environment reduced epithelial damage, lessened the inflammation, and attenuated loss of goblet cells compared to animals housed in a normal environment. Our results also show that brain stimulation by exposure to an enriched environment attenuates inflammation in the intestinal mucosa by preventing epithelial barrier dysfunction through BDNF-mediated expression of cell adhesion molecules. At the molecular level, there is a global change in gene expression and gene regulatory networks as a response to dextran treatment. Interestingly, a Myc-driven gene regulatory network enhanced by colitis is attenuated by exposure to an enriched environment, via downmodulation of Myc protein levels. Together, our results show that brain stimulation by exposure to an enriched environment attenuates inflammation in the gut mucosa by fine-tuning an inflammatory gene expression program, opening new venues of investigation for colitis treatment.

Transcription factors (TFs) are proteins that affect gene expression by binding to regulatory regions of DNA in a sequence specific manner. The binding of TFs to DNA is controlled by many factors, including the DNA sequence, concentration of TF, chromatin accessibility and co-factors. Here, we systematically investigated the binding mechanism of hundreds of TFs by analysing ChIP-seq data with our explainable statistical model, ChIPanalyser. This tool uses as inputs the DNA sequence binding motif; the capacity to distinguish between strong and weak binding sites; the concentration of TF; and chromatin accessibility. We asked whether TFs preferred to bind to DNA in open or dense chromatin conformation and found that approximately one third of TFs are predicted to bind the genome in a DNA accessibility independent fashion. Our model predicted this to be the case when the TF binds to its strongest binding regions in the genome, and only a small number of TFs have the capacity to bind dense chromatin at their weakest binding regions, such as CTCF USF2 and CEBPB. Our study demonstrated that the binding of hundreds of human and mouse TFs is predicted by ChIPanalyser with high accuracy and showed that many TFs can bind dense chromatin.