Hidden modes of DNA binding by human nuclear receptors.
Hidden modes of DNA binding by human nuclear receptors.
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DOI：
10.1038/s41467-023-39577-0
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发表时间：
2023-07-13
影响因子：
16.6
通讯作者：
Ansari, Aseem Z.
中科院分区：
文献类型：
--
作者：
Bhimsaria, Devesh;Rodriguez-Martinez, Jose A.;Mendez-Johnson, Jacqui L.;Ghoshdastidar, Debostuti;Varadarajan, Ashwin;Bansal, Manju;Daniels, Danette L.;Ramanathan, Parameswaran;Ansari, Aseem Z.
人类核受体（NRs）是配体反应转录因子的一个超家族，在细胞功能中起着核心作用。它们的功能失调与许多疾病有关，通过合成配体调节它们活性的能力已经产生了16%的fda批准的药物。NRs调节不同的基因网络，然而它们通常从缺乏已知结合基序的基因组位点起作用。在这里，为了更准确地注释已知和未检测的rna的基因组结合位点，我们使用高通量SELEX来全面绘制所有全长人类rna的DNA结合位点偏好，以及它们的配体。此外，为了识别隐藏在dna -蛋白质相互作用组中的非明显结合位点，我们开发了MinSeq Find，这是一种基于电气工程和数字系统设计中的MinTerm概念的搜索算法。由此产生的MinTerm序列集（MinSeqs）揭示了更有效地注释细胞中nr结合谱的结合位点群。MinSeqs还揭示了与人类疾病相关的52106个单核苷酸多态性产生或破坏的结合位点。通过暗示可用药的NRs是多种人类疾病的隐藏驱动因素，我们的研究结果不仅揭示了NRs的新的生物学作用，而且还为药物再利用和精准医学提供了资源。核受体（NR）是药物反应性的主调控因子。在这里，作者绘制了所有人类nr的DNA结合谱。他们的MinSeq Find算法确定了基因组中被掩盖的NR结合位点，并绘制了与许多疾病相关的约10%的孤儿snp图谱。
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. 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.
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影响因子：
7
作者：
Boyle AP;Hong EL;Hariharan M;Cheng Y;Schaub MA;Kasowski M;Karczewski KJ;Park J;Hitz BC;Weng S;Cherry JM;Snyder M
通讯作者：
Snyder M
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
影响因子：
48
作者：
Isakova, Alina;Groux, Romain;Deplancke, Bart
通讯作者：
Deplancke, Bart
模因套件：用于发现和搜索的工具。
影响因子：
14.9
作者：
Bailey TL;Boden M;Buske FA;Frith M;Grant CE;Clementi L;Ren J;Li WW;Noble WS
通讯作者：
Noble WS
影响因子：
14.9
作者：
Fang B;Mane-Padros D;Bolotin E;Jiang T;Sladek FM
通讯作者：
Sladek FM