Multi-omics and machine learning reveal context-specific gene regulatory activities of PML::RARA in acute promyelocytic leukemia
<p dir="ltr">The PML::RARA fusion protein is the hallmark driver of Acute Promyelocytic Leukemia (APL) and disrupts retinoic acid signaling, leading to wide-scale gene expression changes and uncontrolled proliferation of myeloid precursor cells. While known to be recruited to binding...
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2023
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| _version_ | 1864513507143188480 |
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| author | William Villiers (19482292) |
| author2 | Audrey Kelly (7671395) Xiaohan He (9204173) James Kaufman-Cook (19482295) Abdurrahman Elbasir (9977355) Halima Bensmail (10400) Paul Lavender (7671401) Richard Dillon (9149324) Borbála Mifsud (19482298) Cameron S. Osborne (7244990) |
| author2_role | author author author author author author author author author |
| author_facet | William Villiers (19482292) Audrey Kelly (7671395) Xiaohan He (9204173) James Kaufman-Cook (19482295) Abdurrahman Elbasir (9977355) Halima Bensmail (10400) Paul Lavender (7671401) Richard Dillon (9149324) Borbála Mifsud (19482298) Cameron S. Osborne (7244990) |
| author_role | author |
| dc.creator.none.fl_str_mv | William Villiers (19482292) Audrey Kelly (7671395) Xiaohan He (9204173) James Kaufman-Cook (19482295) Abdurrahman Elbasir (9977355) Halima Bensmail (10400) Paul Lavender (7671401) Richard Dillon (9149324) Borbála Mifsud (19482298) Cameron S. Osborne (7244990) |
| dc.date.none.fl_str_mv | 2023-02-09T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1038/s41467-023-36262-0 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Multi-omics_and_machine_learning_reveal_context-specific_gene_regulatory_activities_of_PML_RARA_in_acute_promyelocytic_leukemia/26830123 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Oncology and carcinogenesis Health sciences Health services and systems Information and computing sciences Machine learning PML::RARA Fusion Protein Acute Promyelocytic Leukemia (APL) Retinoic Acid Signaling Gene Expression Myeloid Precursor Cells Multi-Omics Datasets Machine Learning |
| dc.title.none.fl_str_mv | Multi-omics and machine learning reveal context-specific gene regulatory activities of PML::RARA in acute promyelocytic leukemia |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">The PML::RARA fusion protein is the hallmark driver of Acute Promyelocytic Leukemia (APL) and disrupts retinoic acid signaling, leading to wide-scale gene expression changes and uncontrolled proliferation of myeloid precursor cells. While known to be recruited to binding sites across the genome, its impact on gene regulation and expression is under-explored. Using integrated multi-omics datasets, we characterize the influence of PML::RARA binding on gene expression and regulation in an inducible PML::RARA cell line model and APL patient ex vivo samples. We find that genes whose regulatory elements recruit PML::RARA are not uniformly transcriptionally repressed, as commonly suggested, but also may be upregulated or remain unchanged. We develop a computational machine learning implementation called Regulatory Element Behavior Extraction Learning to deconvolute the complex, local transcription factor binding site environment at PML::RARA bound positions to reveal distinct signatures that modulate how PML::RARA directs the transcriptional response.</p><h2>Other Information</h2><p dir="ltr">Published in: Nature Communications<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41467-023-36262-0" target="_blank">https://dx.doi.org/10.1038/s41467-023-36262-0</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_ef10c044df96820e883d2eb8a4a0d5fb |
| identifier_str_mv | 10.1038/s41467-023-36262-0 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26830123 |
| publishDate | 2023 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Multi-omics and machine learning reveal context-specific gene regulatory activities of PML::RARA in acute promyelocytic leukemiaWilliam Villiers (19482292)Audrey Kelly (7671395)Xiaohan He (9204173)James Kaufman-Cook (19482295)Abdurrahman Elbasir (9977355)Halima Bensmail (10400)Paul Lavender (7671401)Richard Dillon (9149324)Borbála Mifsud (19482298)Cameron S. Osborne (7244990)Biomedical and clinical sciencesOncology and carcinogenesisHealth sciencesHealth services and systemsInformation and computing sciencesMachine learningPML::RARA Fusion ProteinAcute Promyelocytic Leukemia (APL)Retinoic Acid SignalingGene ExpressionMyeloid Precursor CellsMulti-Omics DatasetsMachine Learning<p dir="ltr">The PML::RARA fusion protein is the hallmark driver of Acute Promyelocytic Leukemia (APL) and disrupts retinoic acid signaling, leading to wide-scale gene expression changes and uncontrolled proliferation of myeloid precursor cells. While known to be recruited to binding sites across the genome, its impact on gene regulation and expression is under-explored. Using integrated multi-omics datasets, we characterize the influence of PML::RARA binding on gene expression and regulation in an inducible PML::RARA cell line model and APL patient ex vivo samples. We find that genes whose regulatory elements recruit PML::RARA are not uniformly transcriptionally repressed, as commonly suggested, but also may be upregulated or remain unchanged. We develop a computational machine learning implementation called Regulatory Element Behavior Extraction Learning to deconvolute the complex, local transcription factor binding site environment at PML::RARA bound positions to reveal distinct signatures that modulate how PML::RARA directs the transcriptional response.</p><h2>Other Information</h2><p dir="ltr">Published in: Nature Communications<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41467-023-36262-0" target="_blank">https://dx.doi.org/10.1038/s41467-023-36262-0</a></p>2023-02-09T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1038/s41467-023-36262-0https://figshare.com/articles/journal_contribution/Multi-omics_and_machine_learning_reveal_context-specific_gene_regulatory_activities_of_PML_RARA_in_acute_promyelocytic_leukemia/26830123CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/268301232023-02-09T03:00:00Z |
| spellingShingle | Multi-omics and machine learning reveal context-specific gene regulatory activities of PML::RARA in acute promyelocytic leukemia William Villiers (19482292) Biomedical and clinical sciences Oncology and carcinogenesis Health sciences Health services and systems Information and computing sciences Machine learning PML::RARA Fusion Protein Acute Promyelocytic Leukemia (APL) Retinoic Acid Signaling Gene Expression Myeloid Precursor Cells Multi-Omics Datasets Machine Learning |
| status_str | publishedVersion |
| title | Multi-omics and machine learning reveal context-specific gene regulatory activities of PML::RARA in acute promyelocytic leukemia |
| title_full | Multi-omics and machine learning reveal context-specific gene regulatory activities of PML::RARA in acute promyelocytic leukemia |
| title_fullStr | Multi-omics and machine learning reveal context-specific gene regulatory activities of PML::RARA in acute promyelocytic leukemia |
| title_full_unstemmed | Multi-omics and machine learning reveal context-specific gene regulatory activities of PML::RARA in acute promyelocytic leukemia |
| title_short | Multi-omics and machine learning reveal context-specific gene regulatory activities of PML::RARA in acute promyelocytic leukemia |
| title_sort | Multi-omics and machine learning reveal context-specific gene regulatory activities of PML::RARA in acute promyelocytic leukemia |
| topic | Biomedical and clinical sciences Oncology and carcinogenesis Health sciences Health services and systems Information and computing sciences Machine learning PML::RARA Fusion Protein Acute Promyelocytic Leukemia (APL) Retinoic Acid Signaling Gene Expression Myeloid Precursor Cells Multi-Omics Datasets Machine Learning |