Hidden modes of DNA binding by human nuclear receptors
Abstract 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 dr...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39577-0 |
| _version_ | 1797778817427701760 |
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| author | Devesh Bhimsaria José A. Rodríguez-Martínez Jacqui L. Mendez-Johnson Debostuti Ghoshdastidar Ashwin Varadarajan Manju Bansal Danette L. Daniels Parameswaran Ramanathan Aseem Z. Ansari |
| author_facet | Devesh Bhimsaria José A. Rodríguez-Martínez Jacqui L. Mendez-Johnson Debostuti Ghoshdastidar Ashwin Varadarajan Manju Bansal Danette L. Daniels Parameswaran Ramanathan Aseem Z. Ansari |
| author_sort | Devesh Bhimsaria |
| collection | DOAJ |
| description | Abstract 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 MinTerm sequence set (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. |
| first_indexed | 2024-03-12T23:22:00Z |
| format | Article |
| id | doaj.art-242e27d07a204f70a4df0ed003cf82dd |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-12T23:22:00Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-242e27d07a204f70a4df0ed003cf82dd2023-07-16T11:20:52ZengNature PortfolioNature Communications2041-17232023-07-0114111610.1038/s41467-023-39577-0Hidden modes of DNA binding by human nuclear receptorsDevesh Bhimsaria0José A. Rodríguez-Martínez1Jacqui L. Mendez-Johnson2Debostuti Ghoshdastidar3Ashwin Varadarajan4Manju Bansal5Danette L. Daniels6Parameswaran Ramanathan7Aseem Z. Ansari8Department of Biosciences and Bioengineering, Indian Institute of Technology RoorkeeDepartment of Biology, University of Puerto Rico Río PiedrasPromega CorporationMolecular Biophysics Unit, Indian Institute of ScienceDepartment of Electrical and Computer Engineering, University of Wisconsin–MadisonMolecular Biophysics Unit, Indian Institute of SciencePromega CorporationDepartment of Electrical and Computer Engineering, University of Wisconsin–MadisonDepartment of Chemical Biology and Therapeutics, St. Jude Children’s Research HospitalAbstract 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 MinTerm sequence set (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.https://doi.org/10.1038/s41467-023-39577-0 |
| spellingShingle | Devesh Bhimsaria José A. Rodríguez-Martínez Jacqui L. Mendez-Johnson Debostuti Ghoshdastidar Ashwin Varadarajan Manju Bansal Danette L. Daniels Parameswaran Ramanathan Aseem Z. Ansari Hidden modes of DNA binding by human nuclear receptors Nature Communications |
| title | Hidden modes of DNA binding by human nuclear receptors |
| title_full | Hidden modes of DNA binding by human nuclear receptors |
| title_fullStr | Hidden modes of DNA binding by human nuclear receptors |
| title_full_unstemmed | Hidden modes of DNA binding by human nuclear receptors |
| title_short | Hidden modes of DNA binding by human nuclear receptors |
| title_sort | hidden modes of dna binding by human nuclear receptors |
| url | https://doi.org/10.1038/s41467-023-39577-0 |
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