Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
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
_version_ 1785025844320665600
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
work_keys_str_mv AT weiyanfei stalledoligodendrocytedifferentiationinidhmutantgliomas
AT liguanzhang stalledoligodendrocytedifferentiationinidhmutantgliomas
AT fengjing stalledoligodendrocytedifferentiationinidhmutantgliomas
AT wufan stalledoligodendrocytedifferentiationinidhmutantgliomas
AT zhaozheng stalledoligodendrocytedifferentiationinidhmutantgliomas
AT baozhaoshi stalledoligodendrocytedifferentiationinidhmutantgliomas
AT zhangwei stalledoligodendrocytedifferentiationinidhmutantgliomas
AT suxiaodong stalledoligodendrocytedifferentiationinidhmutantgliomas
AT lijiuyi stalledoligodendrocytedifferentiationinidhmutantgliomas
AT qixueling stalledoligodendrocytedifferentiationinidhmutantgliomas
AT duanzejun stalledoligodendrocytedifferentiationinidhmutantgliomas
AT zhangyunqiu stalledoligodendrocytedifferentiationinidhmutantgliomas
AT vegasandraferreyra stalledoligodendrocytedifferentiationinidhmutantgliomas
AT jakolaasgeirstore stalledoligodendrocytedifferentiationinidhmutantgliomas
AT sunyingyu stalledoligodendrocytedifferentiationinidhmutantgliomas
AT carenhelena stalledoligodendrocytedifferentiationinidhmutantgliomas
AT jiangtao stalledoligodendrocytedifferentiationinidhmutantgliomas
AT fanxiaolong stalledoligodendrocytedifferentiationinidhmutantgliomas