Analysis of long and short enhancers in melanoma cell states
Understanding how enhancers drive cell-type specificity and efficiently identifying them is essential for the development of innovative therapeutic strategies. In melanoma, the melanocytic (MEL) and the mesenchymal-like (MES) states present themselves with different responses to therapy, making the...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/71735 |
| _version_ | 1811199877159321600 |
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| author | David Mauduit Ibrahim Ihsan Taskiran Liesbeth Minnoye Maxime de Waegeneer Valerie Christiaens Gert Hulselmans Jonas Demeulemeester Jasper Wouters Stein Aerts |
| author_facet | David Mauduit Ibrahim Ihsan Taskiran Liesbeth Minnoye Maxime de Waegeneer Valerie Christiaens Gert Hulselmans Jonas Demeulemeester Jasper Wouters Stein Aerts |
| author_sort | David Mauduit |
| collection | DOAJ |
| description | Understanding how enhancers drive cell-type specificity and efficiently identifying them is essential for the development of innovative therapeutic strategies. In melanoma, the melanocytic (MEL) and the mesenchymal-like (MES) states present themselves with different responses to therapy, making the identification of specific enhancers highly relevant. Using massively parallel reporter assays (MPRAs) in a panel of patient-derived melanoma lines (MM lines), we set to identify and decipher melanoma enhancers by first focusing on regions with state-specific H3K27 acetylation close to differentially expressed genes. An in-depth evaluation of those regions was then pursued by investigating the activity of overlapping ATAC-seq peaks along with a full tiling of the acetylated regions with 190 bp sequences. Activity was observed in more than 60% of the selected regions, and we were able to precisely locate the active enhancers within ATAC-seq peaks. Comparison of sequence content with activity, using the deep learning model DeepMEL2, revealed that AP-1 alone is responsible for the MES enhancer activity. In contrast, SOX10 and MITF both influence MEL enhancer function with SOX10 being required to achieve high levels of activity. Overall, our MPRAs shed light on the relationship between long and short sequences in terms of their sequence content, enhancer activity, and specificity across melanoma cell states. |
| first_indexed | 2024-04-12T01:54:57Z |
| format | Article |
| id | doaj.art-8cc6826acf8940b387a34efa788b6d00 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T01:54:57Z |
| publishDate | 2021-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-8cc6826acf8940b387a34efa788b6d002022-12-22T03:52:49ZengeLife Sciences Publications LtdeLife2050-084X2021-12-011010.7554/eLife.71735Analysis of long and short enhancers in melanoma cell statesDavid Mauduit0https://orcid.org/0000-0002-2045-227XIbrahim Ihsan Taskiran1https://orcid.org/0000-0002-5077-5264Liesbeth Minnoye2Maxime de Waegeneer3Valerie Christiaens4Gert Hulselmans5Jonas Demeulemeester6https://orcid.org/0000-0002-2660-2478Jasper Wouters7https://orcid.org/0000-0002-7129-2990Stein Aerts8https://orcid.org/0000-0002-8006-0315VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; KU Leuven, Department of Human Genetics KU Leuven, Leuven, BelgiumVIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; KU Leuven, Department of Human Genetics KU Leuven, Leuven, BelgiumVIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; KU Leuven, Department of Human Genetics KU Leuven, Leuven, BelgiumVIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; KU Leuven, Department of Human Genetics KU Leuven, Leuven, BelgiumVIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; KU Leuven, Department of Human Genetics KU Leuven, Leuven, BelgiumVIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; KU Leuven, Department of Human Genetics KU Leuven, Leuven, BelgiumVIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; KU Leuven, Department of Human Genetics KU Leuven, Leuven, Belgium; Cancer Genomics Laboratory, The Francis Crick Institute, London, United KingdomVIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; KU Leuven, Department of Human Genetics KU Leuven, Leuven, BelgiumVIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; KU Leuven, Department of Human Genetics KU Leuven, Leuven, BelgiumUnderstanding how enhancers drive cell-type specificity and efficiently identifying them is essential for the development of innovative therapeutic strategies. In melanoma, the melanocytic (MEL) and the mesenchymal-like (MES) states present themselves with different responses to therapy, making the identification of specific enhancers highly relevant. Using massively parallel reporter assays (MPRAs) in a panel of patient-derived melanoma lines (MM lines), we set to identify and decipher melanoma enhancers by first focusing on regions with state-specific H3K27 acetylation close to differentially expressed genes. An in-depth evaluation of those regions was then pursued by investigating the activity of overlapping ATAC-seq peaks along with a full tiling of the acetylated regions with 190 bp sequences. Activity was observed in more than 60% of the selected regions, and we were able to precisely locate the active enhancers within ATAC-seq peaks. Comparison of sequence content with activity, using the deep learning model DeepMEL2, revealed that AP-1 alone is responsible for the MES enhancer activity. In contrast, SOX10 and MITF both influence MEL enhancer function with SOX10 being required to achieve high levels of activity. Overall, our MPRAs shed light on the relationship between long and short sequences in terms of their sequence content, enhancer activity, and specificity across melanoma cell states.https://elifesciences.org/articles/71735melanomaenhancersMPRA |
| spellingShingle | David Mauduit Ibrahim Ihsan Taskiran Liesbeth Minnoye Maxime de Waegeneer Valerie Christiaens Gert Hulselmans Jonas Demeulemeester Jasper Wouters Stein Aerts Analysis of long and short enhancers in melanoma cell states eLife melanoma enhancers MPRA |
| title | Analysis of long and short enhancers in melanoma cell states |
| title_full | Analysis of long and short enhancers in melanoma cell states |
| title_fullStr | Analysis of long and short enhancers in melanoma cell states |
| title_full_unstemmed | Analysis of long and short enhancers in melanoma cell states |
| title_short | Analysis of long and short enhancers in melanoma cell states |
| title_sort | analysis of long and short enhancers in melanoma cell states |
| topic | melanoma enhancers MPRA |
| url | https://elifesciences.org/articles/71735 |
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