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Cross-species analysis of enhancer logic using deep learning

Deciphering the genomic regulatory code of enhancers is a key challenge in biology because this code underlies cellular identity. A better understanding of how enhancers work will improve the interpretation of noncoding genome variation and empower the generation of cell type–specific drivers for ge...

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Autores principales: Minnoye, Liesbeth, Taskiran, Ibrahim Ihsan, Mauduit, David, Fazio, Maurizio, Van Aerschot, Linde, Hulselmans, Gert, Christiaens, Valerie, Makhzami, Samira, Seltenhammer, Monika, Karras, Panagiotis, Primot, Aline, Cadieu, Edouard, van Rooijen, Ellen, Marine, Jean-Christophe, Egidy, Giorgia, Ghanem, Ghanem-Elias, Zon, Leonard, Wouters, Jasper, Aerts, Stein
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706731/
https://www.ncbi.nlm.nih.gov/pubmed/32732264
http://dx.doi.org/10.1101/gr.260844.120
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author Minnoye, Liesbeth
Taskiran, Ibrahim Ihsan
Mauduit, David
Fazio, Maurizio
Van Aerschot, Linde
Hulselmans, Gert
Christiaens, Valerie
Makhzami, Samira
Seltenhammer, Monika
Karras, Panagiotis
Primot, Aline
Cadieu, Edouard
van Rooijen, Ellen
Marine, Jean-Christophe
Egidy, Giorgia
Ghanem, Ghanem-Elias
Zon, Leonard
Wouters, Jasper
Aerts, Stein
author_facet Minnoye, Liesbeth
Taskiran, Ibrahim Ihsan
Mauduit, David
Fazio, Maurizio
Van Aerschot, Linde
Hulselmans, Gert
Christiaens, Valerie
Makhzami, Samira
Seltenhammer, Monika
Karras, Panagiotis
Primot, Aline
Cadieu, Edouard
van Rooijen, Ellen
Marine, Jean-Christophe
Egidy, Giorgia
Ghanem, Ghanem-Elias
Zon, Leonard
Wouters, Jasper
Aerts, Stein
author_sort Minnoye, Liesbeth
collection PubMed
description Deciphering the genomic regulatory code of enhancers is a key challenge in biology because this code underlies cellular identity. A better understanding of how enhancers work will improve the interpretation of noncoding genome variation and empower the generation of cell type–specific drivers for gene therapy. Here, we explore the combination of deep learning and cross-species chromatin accessibility profiling to build explainable enhancer models. We apply this strategy to decipher the enhancer code in melanoma, a relevant case study owing to the presence of distinct melanoma cell states. We trained and validated a deep learning model, called DeepMEL, using chromatin accessibility data of 26 melanoma samples across six different species. We show the accuracy of DeepMEL predictions on the CAGI5 challenge, where it significantly outperforms existing models on the melanoma enhancer of IRF4. Next, we exploit DeepMEL to analyze enhancer architectures and identify accurate transcription factor binding sites for the core regulatory complexes in the two different melanoma states, with distinct roles for each transcription factor, in terms of nucleosome displacement or enhancer activation. Finally, DeepMEL identifies orthologous enhancers across distantly related species, where sequence alignment fails, and the model highlights specific nucleotide substitutions that underlie enhancer turnover. DeepMEL can be used from the Kipoi database to predict and optimize candidate enhancers and to prioritize enhancer mutations. In addition, our computational strategy can be applied to other cancer or normal cell types.
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spelling pubmed-77067312020-12-09 Cross-species analysis of enhancer logic using deep learning Minnoye, Liesbeth Taskiran, Ibrahim Ihsan Mauduit, David Fazio, Maurizio Van Aerschot, Linde Hulselmans, Gert Christiaens, Valerie Makhzami, Samira Seltenhammer, Monika Karras, Panagiotis Primot, Aline Cadieu, Edouard van Rooijen, Ellen Marine, Jean-Christophe Egidy, Giorgia Ghanem, Ghanem-Elias Zon, Leonard Wouters, Jasper Aerts, Stein Genome Res Method Deciphering the genomic regulatory code of enhancers is a key challenge in biology because this code underlies cellular identity. A better understanding of how enhancers work will improve the interpretation of noncoding genome variation and empower the generation of cell type–specific drivers for gene therapy. Here, we explore the combination of deep learning and cross-species chromatin accessibility profiling to build explainable enhancer models. We apply this strategy to decipher the enhancer code in melanoma, a relevant case study owing to the presence of distinct melanoma cell states. We trained and validated a deep learning model, called DeepMEL, using chromatin accessibility data of 26 melanoma samples across six different species. We show the accuracy of DeepMEL predictions on the CAGI5 challenge, where it significantly outperforms existing models on the melanoma enhancer of IRF4. Next, we exploit DeepMEL to analyze enhancer architectures and identify accurate transcription factor binding sites for the core regulatory complexes in the two different melanoma states, with distinct roles for each transcription factor, in terms of nucleosome displacement or enhancer activation. Finally, DeepMEL identifies orthologous enhancers across distantly related species, where sequence alignment fails, and the model highlights specific nucleotide substitutions that underlie enhancer turnover. DeepMEL can be used from the Kipoi database to predict and optimize candidate enhancers and to prioritize enhancer mutations. In addition, our computational strategy can be applied to other cancer or normal cell types. Cold Spring Harbor Laboratory Press 2020-12 /pmc/articles/PMC7706731/ /pubmed/32732264 http://dx.doi.org/10.1101/gr.260844.120 Text en © 2020 Minnoye et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
spellingShingle Method
Minnoye, Liesbeth
Taskiran, Ibrahim Ihsan
Mauduit, David
Fazio, Maurizio
Van Aerschot, Linde
Hulselmans, Gert
Christiaens, Valerie
Makhzami, Samira
Seltenhammer, Monika
Karras, Panagiotis
Primot, Aline
Cadieu, Edouard
van Rooijen, Ellen
Marine, Jean-Christophe
Egidy, Giorgia
Ghanem, Ghanem-Elias
Zon, Leonard
Wouters, Jasper
Aerts, Stein
Cross-species analysis of enhancer logic using deep learning
title Cross-species analysis of enhancer logic using deep learning
title_full Cross-species analysis of enhancer logic using deep learning
title_fullStr Cross-species analysis of enhancer logic using deep learning
title_full_unstemmed Cross-species analysis of enhancer logic using deep learning
title_short Cross-species analysis of enhancer logic using deep learning
title_sort cross-species analysis of enhancer logic using deep learning
topic Method
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706731/
https://www.ncbi.nlm.nih.gov/pubmed/32732264
http://dx.doi.org/10.1101/gr.260844.120
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