Transcription factor binding site orientation and order are major drivers of gene regulatory activity
Abstract The gene regulatory code and grammar remain largely unknown, precluding our ability to link phenotype to genotype in regulatory sequences. Here, using a massively parallel reporter assay (MPRA) of 209,440 sequences, we examine all possible pair and triplet combinations, permutations and ori...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-37960-5 |
| _version_ | 1827961225812639744 |
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| author | Ilias Georgakopoulos-Soares Chengyu Deng Vikram Agarwal Candace S. Y. Chan Jingjing Zhao Fumitaka Inoue Nadav Ahituv |
| author_facet | Ilias Georgakopoulos-Soares Chengyu Deng Vikram Agarwal Candace S. Y. Chan Jingjing Zhao Fumitaka Inoue Nadav Ahituv |
| author_sort | Ilias Georgakopoulos-Soares |
| collection | DOAJ |
| description | Abstract The gene regulatory code and grammar remain largely unknown, precluding our ability to link phenotype to genotype in regulatory sequences. Here, using a massively parallel reporter assay (MPRA) of 209,440 sequences, we examine all possible pair and triplet combinations, permutations and orientations of eighteen liver-associated transcription factor binding sites (TFBS). We find that TFBS orientation and order have a major effect on gene regulatory activity. Corroborating these results with genomic analyses, we find clear human promoter TFBS orientation biases and similar TFBS orientation and order transcriptional effects in an MPRA that tested 164,307 liver candidate regulatory elements. Additionally, by adding TFBS orientation to a model that predicts expression from sequence we improve performance by 7.7%. Collectively, our results show that TFBS orientation and order have a significant effect on gene regulatory activity and need to be considered when analyzing the functional effect of variants on the activity of these sequences. |
| first_indexed | 2024-04-09T16:23:19Z |
| format | Article |
| id | doaj.art-e639a6096e204e71ac522a5bd70fb3de |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-09T16:23:19Z |
| publishDate | 2023-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-e639a6096e204e71ac522a5bd70fb3de2023-04-23T11:23:24ZengNature PortfolioNature Communications2041-17232023-04-0114111610.1038/s41467-023-37960-5Transcription factor binding site orientation and order are major drivers of gene regulatory activityIlias Georgakopoulos-Soares0Chengyu Deng1Vikram Agarwal2Candace S. Y. Chan3Jingjing Zhao4Fumitaka Inoue5Nadav Ahituv6Department of Bioengineering and Therapeutic Sciences, University of California San FranciscoDepartment of Bioengineering and Therapeutic Sciences, University of California San FranciscomRNA Center of Excellence, Sanofi Pasteur Inc.Department of Bioengineering and Therapeutic Sciences, University of California San FranciscoDepartment of Bioengineering and Therapeutic Sciences, University of California San FranciscoInstitute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto UniversityDepartment of Bioengineering and Therapeutic Sciences, University of California San FranciscoAbstract The gene regulatory code and grammar remain largely unknown, precluding our ability to link phenotype to genotype in regulatory sequences. Here, using a massively parallel reporter assay (MPRA) of 209,440 sequences, we examine all possible pair and triplet combinations, permutations and orientations of eighteen liver-associated transcription factor binding sites (TFBS). We find that TFBS orientation and order have a major effect on gene regulatory activity. Corroborating these results with genomic analyses, we find clear human promoter TFBS orientation biases and similar TFBS orientation and order transcriptional effects in an MPRA that tested 164,307 liver candidate regulatory elements. Additionally, by adding TFBS orientation to a model that predicts expression from sequence we improve performance by 7.7%. Collectively, our results show that TFBS orientation and order have a significant effect on gene regulatory activity and need to be considered when analyzing the functional effect of variants on the activity of these sequences.https://doi.org/10.1038/s41467-023-37960-5 |
| spellingShingle | Ilias Georgakopoulos-Soares Chengyu Deng Vikram Agarwal Candace S. Y. Chan Jingjing Zhao Fumitaka Inoue Nadav Ahituv Transcription factor binding site orientation and order are major drivers of gene regulatory activity Nature Communications |
| title | Transcription factor binding site orientation and order are major drivers of gene regulatory activity |
| title_full | Transcription factor binding site orientation and order are major drivers of gene regulatory activity |
| title_fullStr | Transcription factor binding site orientation and order are major drivers of gene regulatory activity |
| title_full_unstemmed | Transcription factor binding site orientation and order are major drivers of gene regulatory activity |
| title_short | Transcription factor binding site orientation and order are major drivers of gene regulatory activity |
| title_sort | transcription factor binding site orientation and order are major drivers of gene regulatory activity |
| url | https://doi.org/10.1038/s41467-023-37960-5 |
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