Characterization of sequence determinants of enhancer function using natural genetic variation
Sequence variation in enhancers that control cell-type-specific gene transcription contributes significantly to phenotypic variation within human populations. However, it remains difficult to predict precisely the effect of any given sequence variant on enhancer function due to the complexity of DNA...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-08-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/76500 |
| _version_ | 1811225745762025472 |
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| author | Marty G Yang Emi Ling Christopher J Cowley Michael E Greenberg Thomas Vierbuchen |
| author_facet | Marty G Yang Emi Ling Christopher J Cowley Michael E Greenberg Thomas Vierbuchen |
| author_sort | Marty G Yang |
| collection | DOAJ |
| description | Sequence variation in enhancers that control cell-type-specific gene transcription contributes significantly to phenotypic variation within human populations. However, it remains difficult to predict precisely the effect of any given sequence variant on enhancer function due to the complexity of DNA sequence motifs that determine transcription factor (TF) binding to enhancers in their native genomic context. Using F1-hybrid cells derived from crosses between distantly related inbred strains of mice, we identified thousands of enhancers with allele-specific TF binding and/or activity. We find that genetic variants located within the central region of enhancers are most likely to alter TF binding and enhancer activity. We observe that the AP-1 family of TFs (Fos/Jun) are frequently required for binding of TEAD TFs and for enhancer function. However, many sequence variants outside of core motifs for AP-1 and TEAD also impact enhancer function, including sequences flanking core TF motifs and AP-1 half sites. Taken together, these data represent one of the most comprehensive assessments of allele-specific TF binding and enhancer function to date and reveal how sequence changes at enhancers alter their function across evolutionary timescales. |
| first_indexed | 2024-04-12T09:12:36Z |
| format | Article |
| id | doaj.art-637ec108529642a3a214676a933beab7 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T09:12:36Z |
| publishDate | 2022-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-637ec108529642a3a214676a933beab72022-12-22T03:38:56ZengeLife Sciences Publications LtdeLife2050-084X2022-08-011110.7554/eLife.76500Characterization of sequence determinants of enhancer function using natural genetic variationMarty G Yang0https://orcid.org/0000-0001-5788-3092Emi Ling1https://orcid.org/0000-0001-5287-0284Christopher J Cowley2Michael E Greenberg3https://orcid.org/0000-0003-1380-2160Thomas Vierbuchen4https://orcid.org/0000-0002-5690-5680Department of Neurobiology, Harvard Medical School, Boston, United States; Program in Neuroscience, Harvard Medical School, Boston, United StatesDepartment of Neurobiology, Harvard Medical School, Boston, United StatesDepartment of Neurobiology, Harvard Medical School, Boston, United StatesDepartment of Neurobiology, Harvard Medical School, Boston, United StatesDevelopmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, United States; Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, New York, United StatesSequence variation in enhancers that control cell-type-specific gene transcription contributes significantly to phenotypic variation within human populations. However, it remains difficult to predict precisely the effect of any given sequence variant on enhancer function due to the complexity of DNA sequence motifs that determine transcription factor (TF) binding to enhancers in their native genomic context. Using F1-hybrid cells derived from crosses between distantly related inbred strains of mice, we identified thousands of enhancers with allele-specific TF binding and/or activity. We find that genetic variants located within the central region of enhancers are most likely to alter TF binding and enhancer activity. We observe that the AP-1 family of TFs (Fos/Jun) are frequently required for binding of TEAD TFs and for enhancer function. However, many sequence variants outside of core motifs for AP-1 and TEAD also impact enhancer function, including sequences flanking core TF motifs and AP-1 half sites. Taken together, these data represent one of the most comprehensive assessments of allele-specific TF binding and enhancer function to date and reveal how sequence changes at enhancers alter their function across evolutionary timescales.https://elifesciences.org/articles/76500gene regulationtranscription factorsenhancers |
| spellingShingle | Marty G Yang Emi Ling Christopher J Cowley Michael E Greenberg Thomas Vierbuchen Characterization of sequence determinants of enhancer function using natural genetic variation eLife gene regulation transcription factors enhancers |
| title | Characterization of sequence determinants of enhancer function using natural genetic variation |
| title_full | Characterization of sequence determinants of enhancer function using natural genetic variation |
| title_fullStr | Characterization of sequence determinants of enhancer function using natural genetic variation |
| title_full_unstemmed | Characterization of sequence determinants of enhancer function using natural genetic variation |
| title_short | Characterization of sequence determinants of enhancer function using natural genetic variation |
| title_sort | characterization of sequence determinants of enhancer function using natural genetic variation |
| topic | gene regulation transcription factors enhancers |
| url | https://elifesciences.org/articles/76500 |
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