Hidden modes of DNA binding by human nuclear receptors

• Published in: Nature communications 2023-07, Vol.14 (1), p.4179-16, Article 4179
• Main Authors: Bhimsaria, Devesh, Rodríguez-Martínez, José A., Mendez-Johnson, Jacqui L., Ghoshdastidar, Debostuti, Varadarajan, Ashwin, Bansal, Manju, Daniels, Danette L., Ramanathan, Parameswaran, Ansari, Aseem Z.
• Format: Article
• Language: English
• Subjects: 49/23; 631/114; 631/92/555; 631/92/610; 82/80; Algorithms; Binding sites; Binding Sites - genetics; Deoxyribonucleic acid; Digital systems; DNA; DNA - metabolism; Gene mapping; Genomics; Humanities and Social Sciences; Humans; Ligands; multidisciplinary; Nuclear receptors; Nucleotides; Precision medicine; Receptors; Receptors, Cytoplasmic and Nuclear - genetics; Science; Science (multidisciplinary); Search algorithms; Single-nucleotide polymorphism; Systems design; Transcription Factors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-39577-0

Human nuclear receptors (NRs) are a superfamily of ligand-responsive transcription factors that have central roles in cellular function. Their malfunction is linked to numerous diseases, and the ability to modulate their activity with synthetic ligands has yielded 16% of all FDA-approved drugs. NRs regulate distinct gene networks, however they often function from genomic sites that lack known binding motifs. Here, to annotate genomic binding sites of known and unexamined NRs more accurately, we use high-throughput SELEX to comprehensively map DNA binding site preferences of all full-length human NRs, in complex with their ligands. Furthermore, to identify non-obvious binding sites buried in DNA–protein interactomes, we develop MinSeq Find , a search algorithm based on the MinTerm concept from electrical engineering and digital systems design. The resulting Min Term seq uence s et (MinSeqs) reveal a constellation of binding sites that more effectively annotate NR-binding profiles in cells. MinSeqs also unmask binding sites created or disrupted by 52,106 single-nucleotide polymorphisms associated with human diseases. By implicating druggable NRs as hidden drivers of multiple human diseases, our results not only reveal new biological roles of NRs, but they also provide a resource for drug-repurposing and precision medicine. Nuclear receptors (NR) are drug-responsive master regulators. Here, authors map DNA binding profiles of all human NRs. Their MinSeq Find algorithm identifies masked NR binding sites in genomes and maps ~10% of orphan SNPs linked to numerous diseases.