In silico prediction of the transcription factor-enhancer interaction as a first stage of axonal growth regulation

The development of neurodegenerative diseases is associated with proper neuronal circuit formation, axonal guidance. The DCC receptor (deleted in colorectal cancer / colorectal cancer suppressor) and SHH (sonic hedgehog protein) are among the key regulators of axonal guidance.Aim. Interaction prediction of specific enhancer regions of DCC and SHH genes with respectively annotated transcription factors.Materials and methods. An in silico study was performed. The iEnhancer-2L and ES-ARCNN algorithms were selected to estimate enhancer sequence strength. The interaction between transcription factor and enhancer sequence was assessed using the molecular docking method. The enhancer sequence of DCC and SHH protein genes were taken from the NCBI open-source database in FASTA format. Ensembl database was used for enhancer mapping, GeneCards was used for screening and selection of potentially appropriate enhancers and transcription factors associated with these enhancers. The structures of transcription factors as well as their DNA-binding domains were taken from the UniProtKB/Swiss-prot database. An HDOCK scoring function was used as a metric for assessing the possibility of interaction of the target gene transcription factor with associated enhancer sequence.Results. The results showed that the interactions of transcription factor NANOG with the DCC gene enhancer sequence and the interaction of transcription factor CEBPA with the SHH gene enhancer sequence predicted by molecular docking method are potentially possible. The iEnhancer-2L and ES-ARCNN algorithms predicted the enhancer sequence of the SHH gene as strong one. The enhancer sequence of the DCC gene was estimated as strong in the iEnhancer-2L algorithm and as weak in ES-ARCNN. Binding of the DCC gene enhancer sequence to the transcription factor NANOG at 1–206 bp and 686–885 bp sites is the most probable, binding of the SHH gene enhancer sequence to the transcription factor CEBPA at 1–500 bp (HDOCK limitation of 500 bp) is possible.Conclusion. In silico techniques applied in this study demonstrated satisfactory results of predicting the interaction of the transcription factor with the enhancer sequence. Limitations of the current techniques is the lack of consideration of specific transcription factor binding sites. This drawback can be eliminated by implementing an ab initio molecular dynamics simulations into the present pipeline.