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Stalled oligodendrocyte differentiation in IDH-mutant gliomas
BACKGROUND: Roughly 50% of adult gliomas harbor isocitrate dehydrogenase (IDH) mutations. According to the 2021 WHO classification guideline, these gliomas are diagnosed as astrocytomas, harboring no 1p19q co-deletion, or oligodendrogliomas, harboring 1p19q co-deletion. Recent studies report that ID...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10103394/ https://www.ncbi.nlm.nih.gov/pubmed/37055795 http://dx.doi.org/10.1186/s13073-023-01175-6 |
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author | Wei, Yanfei Li, Guanzhang Feng, Jing Wu, Fan Zhao, Zheng Bao, Zhaoshi Zhang, Wei Su, Xiaodong Li, Jiuyi Qi, Xueling Duan, Zejun Zhang, Yunqiu Vega, Sandra Ferreyra Jakola, Asgeir Store Sun, Yingyu Carén, Helena Jiang, Tao Fan, Xiaolong |
author_facet | Wei, Yanfei Li, Guanzhang Feng, Jing Wu, Fan Zhao, Zheng Bao, Zhaoshi Zhang, Wei Su, Xiaodong Li, Jiuyi Qi, Xueling Duan, Zejun Zhang, Yunqiu Vega, Sandra Ferreyra Jakola, Asgeir Store Sun, Yingyu Carén, Helena Jiang, Tao Fan, Xiaolong |
author_sort | Wei, Yanfei |
collection | PubMed |
description | BACKGROUND: Roughly 50% of adult gliomas harbor isocitrate dehydrogenase (IDH) mutations. According to the 2021 WHO classification guideline, these gliomas are diagnosed as astrocytomas, harboring no 1p19q co-deletion, or oligodendrogliomas, harboring 1p19q co-deletion. Recent studies report that IDH-mutant gliomas share a common developmental hierarchy. However, the neural lineages and differentiation stages in IDH-mutant gliomas remain inadequately characterized. METHODS: Using bulk transcriptomes and single-cell transcriptomes, we identified genes enriched in IDH-mutant gliomas with or without 1p19q co-deletion, we also assessed the expression pattern of stage-specific signatures and key regulators of oligodendrocyte lineage differentiation. We compared the expression of oligodendrocyte lineage stage-specific markers between quiescent and proliferating malignant single cells. The gene expression profiles were validated using RNAscope analysis and myelin staining and were further substantiated using data of DNA methylation and single-cell ATAC-seq. As a control, we assessed the expression pattern of astrocyte lineage markers. RESULTS: Genes concordantly enriched in both subtypes of IDH-mutant gliomas are upregulated in oligodendrocyte progenitor cells (OPC). Signatures of early stages of oligodendrocyte lineage and key regulators of OPC specification and maintenance are enriched in all IDH-mutant gliomas. In contrast, signature of myelin-forming oligodendrocytes, myelination regulators, and myelin components are significantly down-regulated or absent in IDH-mutant gliomas. Further, single-cell transcriptomes of IDH-mutant gliomas are similar to OPC and differentiation-committed oligodendrocyte progenitors, but not to myelinating oligodendrocyte. Most IDH-mutant glioma cells are quiescent; quiescent cells and proliferating cells resemble the same differentiation stage of oligodendrocyte lineage. Mirroring the gene expression profiles along the oligodendrocyte lineage, analyses of DNA methylation and single-cell ATAC-seq data demonstrate that genes of myelination regulators and myelin components are hypermethylated and show inaccessible chromatin status, whereas regulators of OPC specification and maintenance are hypomethylated and show open chromatin status. Markers of astrocyte precursors are not enriched in IDH-mutant gliomas. CONCLUSIONS: Our studies show that despite differences in clinical manifestation and genomic alterations, all IDH-mutant gliomas resemble early stages of oligodendrocyte lineage and are stalled in oligodendrocyte differentiation due to blocked myelination program. These findings provide a framework to accommodate biological features and therapy development for IDH-mutant gliomas. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-023-01175-6. |
format | Online Article Text |
id | pubmed-10103394 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-101033942023-04-15 Stalled oligodendrocyte differentiation in IDH-mutant gliomas Wei, Yanfei Li, Guanzhang Feng, Jing Wu, Fan Zhao, Zheng Bao, Zhaoshi Zhang, Wei Su, Xiaodong Li, Jiuyi Qi, Xueling Duan, Zejun Zhang, Yunqiu Vega, Sandra Ferreyra Jakola, Asgeir Store Sun, Yingyu Carén, Helena Jiang, Tao Fan, Xiaolong Genome Med Research BACKGROUND: Roughly 50% of adult gliomas harbor isocitrate dehydrogenase (IDH) mutations. According to the 2021 WHO classification guideline, these gliomas are diagnosed as astrocytomas, harboring no 1p19q co-deletion, or oligodendrogliomas, harboring 1p19q co-deletion. Recent studies report that IDH-mutant gliomas share a common developmental hierarchy. However, the neural lineages and differentiation stages in IDH-mutant gliomas remain inadequately characterized. METHODS: Using bulk transcriptomes and single-cell transcriptomes, we identified genes enriched in IDH-mutant gliomas with or without 1p19q co-deletion, we also assessed the expression pattern of stage-specific signatures and key regulators of oligodendrocyte lineage differentiation. We compared the expression of oligodendrocyte lineage stage-specific markers between quiescent and proliferating malignant single cells. The gene expression profiles were validated using RNAscope analysis and myelin staining and were further substantiated using data of DNA methylation and single-cell ATAC-seq. As a control, we assessed the expression pattern of astrocyte lineage markers. RESULTS: Genes concordantly enriched in both subtypes of IDH-mutant gliomas are upregulated in oligodendrocyte progenitor cells (OPC). Signatures of early stages of oligodendrocyte lineage and key regulators of OPC specification and maintenance are enriched in all IDH-mutant gliomas. In contrast, signature of myelin-forming oligodendrocytes, myelination regulators, and myelin components are significantly down-regulated or absent in IDH-mutant gliomas. Further, single-cell transcriptomes of IDH-mutant gliomas are similar to OPC and differentiation-committed oligodendrocyte progenitors, but not to myelinating oligodendrocyte. Most IDH-mutant glioma cells are quiescent; quiescent cells and proliferating cells resemble the same differentiation stage of oligodendrocyte lineage. Mirroring the gene expression profiles along the oligodendrocyte lineage, analyses of DNA methylation and single-cell ATAC-seq data demonstrate that genes of myelination regulators and myelin components are hypermethylated and show inaccessible chromatin status, whereas regulators of OPC specification and maintenance are hypomethylated and show open chromatin status. Markers of astrocyte precursors are not enriched in IDH-mutant gliomas. CONCLUSIONS: Our studies show that despite differences in clinical manifestation and genomic alterations, all IDH-mutant gliomas resemble early stages of oligodendrocyte lineage and are stalled in oligodendrocyte differentiation due to blocked myelination program. These findings provide a framework to accommodate biological features and therapy development for IDH-mutant gliomas. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-023-01175-6. BioMed Central 2023-04-13 /pmc/articles/PMC10103394/ /pubmed/37055795 http://dx.doi.org/10.1186/s13073-023-01175-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Wei, Yanfei Li, Guanzhang Feng, Jing Wu, Fan Zhao, Zheng Bao, Zhaoshi Zhang, Wei Su, Xiaodong Li, Jiuyi Qi, Xueling Duan, Zejun Zhang, Yunqiu Vega, Sandra Ferreyra Jakola, Asgeir Store Sun, Yingyu Carén, Helena Jiang, Tao Fan, Xiaolong Stalled oligodendrocyte differentiation in IDH-mutant gliomas |
title | Stalled oligodendrocyte differentiation in IDH-mutant gliomas |
title_full | Stalled oligodendrocyte differentiation in IDH-mutant gliomas |
title_fullStr | Stalled oligodendrocyte differentiation in IDH-mutant gliomas |
title_full_unstemmed | Stalled oligodendrocyte differentiation in IDH-mutant gliomas |
title_short | Stalled oligodendrocyte differentiation in IDH-mutant gliomas |
title_sort | stalled oligodendrocyte differentiation in idh-mutant gliomas |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10103394/ https://www.ncbi.nlm.nih.gov/pubmed/37055795 http://dx.doi.org/10.1186/s13073-023-01175-6 |
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