Abundant repressor binding sites in human enhancers are associated with the fine-tuning of gene regulation
Summary: The regulation of gene expression relies on the coordinated action of transcription factors (TFs) at enhancers, including both activator and repressor TFs. We employed deep learning (DL) to dissect HepG2 enhancers into positive (PAR), negative (NAR), and neutral activity regions. Sharpr-MPR...
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Elsevier
2025-01-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224028852 |
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| author | Wei Song Ivan Ovcharenko |
| author_facet | Wei Song Ivan Ovcharenko |
| author_sort | Wei Song |
| collection | DOAJ |
| description | Summary: The regulation of gene expression relies on the coordinated action of transcription factors (TFs) at enhancers, including both activator and repressor TFs. We employed deep learning (DL) to dissect HepG2 enhancers into positive (PAR), negative (NAR), and neutral activity regions. Sharpr-MPRA and STARR-seq highlight the dichotomy impact of NARs and PARs on modulating and catalyzing the activity of enhancers, respectively. Approximately 22% of HepG2 enhancers, termed ''repressive impact enhancers'' (RIEs), are predominantly populated by NARs and transcriptional repression motifs. Genes flanking RIEs exhibit a stage-specific decline in expression during late development, suggesting RIEs' role in trimming enhancer activities. About 16.7% of human NARs emerge from neutral rhesus macaque DNA. This gain of repressor binding sites in RIEs is associated with a 30% decrease in the average expression of flanking genes in humans compared to rhesus macaque. Our work reveals modulated enhancer activity and adaptable gene regulation through the evolutionary dynamics of TF binding sites. |
| format | Article |
| id | doaj-art-369e32e50eb0445fa0df6d81a6d91933 |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-369e32e50eb0445fa0df6d81a6d919332025-01-08T04:53:18ZengElsevieriScience2589-00422025-01-01281111658Abundant repressor binding sites in human enhancers are associated with the fine-tuning of gene regulationWei Song0Ivan Ovcharenko1Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USAComputational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA; Corresponding authorSummary: The regulation of gene expression relies on the coordinated action of transcription factors (TFs) at enhancers, including both activator and repressor TFs. We employed deep learning (DL) to dissect HepG2 enhancers into positive (PAR), negative (NAR), and neutral activity regions. Sharpr-MPRA and STARR-seq highlight the dichotomy impact of NARs and PARs on modulating and catalyzing the activity of enhancers, respectively. Approximately 22% of HepG2 enhancers, termed ''repressive impact enhancers'' (RIEs), are predominantly populated by NARs and transcriptional repression motifs. Genes flanking RIEs exhibit a stage-specific decline in expression during late development, suggesting RIEs' role in trimming enhancer activities. About 16.7% of human NARs emerge from neutral rhesus macaque DNA. This gain of repressor binding sites in RIEs is associated with a 30% decrease in the average expression of flanking genes in humans compared to rhesus macaque. Our work reveals modulated enhancer activity and adaptable gene regulation through the evolutionary dynamics of TF binding sites.http://www.sciencedirect.com/science/article/pii/S2589004224028852Molecular mechanism of gene regulationBiocomputational methodIn silico biology |
| spellingShingle | Wei Song Ivan Ovcharenko Abundant repressor binding sites in human enhancers are associated with the fine-tuning of gene regulation iScience Molecular mechanism of gene regulation Biocomputational method In silico biology |
| title | Abundant repressor binding sites in human enhancers are associated with the fine-tuning of gene regulation |
| title_full | Abundant repressor binding sites in human enhancers are associated with the fine-tuning of gene regulation |
| title_fullStr | Abundant repressor binding sites in human enhancers are associated with the fine-tuning of gene regulation |
| title_full_unstemmed | Abundant repressor binding sites in human enhancers are associated with the fine-tuning of gene regulation |
| title_short | Abundant repressor binding sites in human enhancers are associated with the fine-tuning of gene regulation |
| title_sort | abundant repressor binding sites in human enhancers are associated with the fine tuning of gene regulation |
| topic | Molecular mechanism of gene regulation Biocomputational method In silico biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224028852 |
| work_keys_str_mv | AT weisong abundantrepressorbindingsitesinhumanenhancersareassociatedwiththefinetuningofgeneregulation AT ivanovcharenko abundantrepressorbindingsitesinhumanenhancersareassociatedwiththefinetuningofgeneregulation |