Discovery of candidate functional non-coding mutations in acute myeloid leukemia using single-cell chromatin accessibility sequencing
Abstract Mutations and gene rearrangements are crucial for the diagnosis and subtyping of acute myeloid leukemia (AML). However, the contribution of non-coding genetic variants, particularly those within cis-regulatory elements (CREs), to AML pathophysiology and heterogeneity remains poorly understo...
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Nature Portfolio
2025-05-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08257-8 |
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| author | Ming Zhu Jiali Zhu Zhijuan Zhu Yiding Yang Jinxian Dai Hua Li Nainong Li Jialiang Huang |
| author_facet | Ming Zhu Jiali Zhu Zhijuan Zhu Yiding Yang Jinxian Dai Hua Li Nainong Li Jialiang Huang |
| author_sort | Ming Zhu |
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| description | Abstract Mutations and gene rearrangements are crucial for the diagnosis and subtyping of acute myeloid leukemia (AML). However, the contribution of non-coding genetic variants, particularly those within cis-regulatory elements (CREs), to AML pathophysiology and heterogeneity remains poorly understood. In this study, we characterize the single-cell chromatin accessibility landscapes of 10 bone marrow samples from AML patients at diagnosis. Additionally, we develop eMut, an integrated computational pipeline for detecting, imputing, and functionally characterizing non-coding mutations in CREs at the single-cell level. Our analysis identifies 2878 potential somatic non-coding mutations, highlighting the extensive mutational heterogeneity in the non-coding genome of AML patients, with recurrent non-coding mutations displaying cell type-specific patterns. We show that mutated CREs are enriched with blood-related genetic variants, potentially linked to AML-associated genes, and harbor a higher abundance of functional CREs, suggesting their functional relevance in leukemogenesis. Importantly, we pinpoint candidate functional non-coding mutations that associate with alteration of target gene expression in AML. Collectively, our work provides a comprehensive resource of single-cell chromatin accessibility in AML and introduces an integrative approach to identify candidate functional non-coding mutations contributing to cellular heterogeneity in AML. |
| format | Article |
| id | doaj-art-7daf0445d8e144d3b734f1a912d2b93d |
| institution | OA Journals |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| series | Communications Biology |
| spelling | doaj-art-7daf0445d8e144d3b734f1a912d2b93d2025-08-20T02:03:32ZengNature PortfolioCommunications Biology2399-36422025-05-018111310.1038/s42003-025-08257-8Discovery of candidate functional non-coding mutations in acute myeloid leukemia using single-cell chromatin accessibility sequencingMing Zhu0Jiali Zhu1Zhijuan Zhu2Yiding Yang3Jinxian Dai4Hua Li5Nainong Li6Jialiang Huang7State Key Laboratory of Cellular Stress Biology, Xiang’an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, Xiang’an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen UniversityHematopoietic Stem Cell Transplantation Center, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Department of Hematology, Fujian Medical University Union Hospital, No.29 Xinquan Street, Gulou DistrictState Key Laboratory of Cellular Stress Biology, Xiang’an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, Xiang’an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen UniversityHematopoietic Stem Cell Transplantation Center, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Department of Hematology, Fujian Medical University Union Hospital, No.29 Xinquan Street, Gulou DistrictHematopoietic Stem Cell Transplantation Center, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Department of Hematology, Fujian Medical University Union Hospital, No.29 Xinquan Street, Gulou DistrictState Key Laboratory of Cellular Stress Biology, Xiang’an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen UniversityAbstract Mutations and gene rearrangements are crucial for the diagnosis and subtyping of acute myeloid leukemia (AML). However, the contribution of non-coding genetic variants, particularly those within cis-regulatory elements (CREs), to AML pathophysiology and heterogeneity remains poorly understood. In this study, we characterize the single-cell chromatin accessibility landscapes of 10 bone marrow samples from AML patients at diagnosis. Additionally, we develop eMut, an integrated computational pipeline for detecting, imputing, and functionally characterizing non-coding mutations in CREs at the single-cell level. Our analysis identifies 2878 potential somatic non-coding mutations, highlighting the extensive mutational heterogeneity in the non-coding genome of AML patients, with recurrent non-coding mutations displaying cell type-specific patterns. We show that mutated CREs are enriched with blood-related genetic variants, potentially linked to AML-associated genes, and harbor a higher abundance of functional CREs, suggesting their functional relevance in leukemogenesis. Importantly, we pinpoint candidate functional non-coding mutations that associate with alteration of target gene expression in AML. Collectively, our work provides a comprehensive resource of single-cell chromatin accessibility in AML and introduces an integrative approach to identify candidate functional non-coding mutations contributing to cellular heterogeneity in AML.https://doi.org/10.1038/s42003-025-08257-8 |
| spellingShingle | Ming Zhu Jiali Zhu Zhijuan Zhu Yiding Yang Jinxian Dai Hua Li Nainong Li Jialiang Huang Discovery of candidate functional non-coding mutations in acute myeloid leukemia using single-cell chromatin accessibility sequencing Communications Biology |
| title | Discovery of candidate functional non-coding mutations in acute myeloid leukemia using single-cell chromatin accessibility sequencing |
| title_full | Discovery of candidate functional non-coding mutations in acute myeloid leukemia using single-cell chromatin accessibility sequencing |
| title_fullStr | Discovery of candidate functional non-coding mutations in acute myeloid leukemia using single-cell chromatin accessibility sequencing |
| title_full_unstemmed | Discovery of candidate functional non-coding mutations in acute myeloid leukemia using single-cell chromatin accessibility sequencing |
| title_short | Discovery of candidate functional non-coding mutations in acute myeloid leukemia using single-cell chromatin accessibility sequencing |
| title_sort | discovery of candidate functional non coding mutations in acute myeloid leukemia using single cell chromatin accessibility sequencing |
| url | https://doi.org/10.1038/s42003-025-08257-8 |
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