Uncovering human transcription factor interactions associated with genetic variants, novel DNA motifs, and repetitive elements using enhanced yeast one-hybrid assays
Carrasco Pro, Sebastian
Fuxman Bass, Juan
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Citation (published version)Shaleen Shrestha, Jared Sewell, Clarissa Santoso, Elena Forchielli, Sebastian Carrasco Pro, Melissa Martinez, Juan Fuxman Bass. "Uncovering human transcription factor interactions associated with genetic variants, novel DNA motifs, and repetitive elements using enhanced yeast one-hybrid assays." BioRxiv, https://doi.org/10.1101/459305 (bioRxiv preprint first posted online Nov. 1, 2018.)
Identifying transcription factor (TF) binding to noncoding variants, uncharacterized DNA motifs, and repetitive genomic elements has been difficult due to technical and computational challenges. Indeed, current experimental methods such as chromatin immunoprecipitation are capable of only testing one TF at a time and motif prediction algorithms often lead to false positive and false negative predictions. Here, we address these limitations by developing two approaches based on enhanced yeast one-hybrid assays. The first approach allows to interrogate the binding of >1,000 human TFs to single nucleotide variant alleles, short insertions and deletions (indels), and novel DNA motifs; while the second approach allows for the identification of TFs that bind to repetitive DNA elements. Using the former approach, we identified gain of TF interactions to a GG→AA mutation in the TERT promoter and an 18 bp indel in the TAL1 super-enhancer, both of which are associated with cancer, and identified the TFs that bind to three uncharacterized DNA motifs identified by the ENCODE Project in footprinting assays. Using the latter approach, we detected the binding of 75 TFs to the highly repetitive Alu elements. We anticipate that these approaches will expand our capabilities to study genetic variation and under-characterized genomic regions.
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