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H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis

Lys-27-Met mutations in histone 3 genes (H3K27M) characterize a subgroup of deadly gliomas and decrease genome-wide H3K27 trimethylation. Here we use primary H3K27M tumor lines and isogenic CRISPR-edited controls to assess H3K27M effects in vitro and in vivo. We find that whereas H3K27me3 and H3K27m...

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Autores principales: Harutyunyan, Ashot S., Krug, Brian, Chen, Haifen, Papillon-Cavanagh, Simon, Zeinieh, Michele, De Jay, Nicolas, Deshmukh, Shriya, Chen, Carol C. L., Belle, Jad, Mikael, Leonie G., Marchione, Dylan M., Li, Rui, Nikbakht, Hamid, Hu, Bo, Cagnone, Gael, Cheung, Warren A., Mohammadnia, Abdulshakour, Bechet, Denise, Faury, Damien, McConechy, Melissa K, Pathania, Manav, Jain, Siddhant U., Ellezam, Benjamin, Weil, Alexander G., Montpetit, Alexandre, Salomoni, Paolo, Pastinen, Tomi, Lu, Chao, Lewis, Peter W., Garcia, Benjamin A., Kleinman, Claudia L., Jabado, Nada, Majewski, Jacek
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425035/
https://www.ncbi.nlm.nih.gov/pubmed/30890717
http://dx.doi.org/10.1038/s41467-019-09140-x
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author Harutyunyan, Ashot S.
Krug, Brian
Chen, Haifen
Papillon-Cavanagh, Simon
Zeinieh, Michele
De Jay, Nicolas
Deshmukh, Shriya
Chen, Carol C. L.
Belle, Jad
Mikael, Leonie G.
Marchione, Dylan M.
Li, Rui
Nikbakht, Hamid
Hu, Bo
Cagnone, Gael
Cheung, Warren A.
Mohammadnia, Abdulshakour
Bechet, Denise
Faury, Damien
McConechy, Melissa K
Pathania, Manav
Jain, Siddhant U.
Ellezam, Benjamin
Weil, Alexander G.
Montpetit, Alexandre
Salomoni, Paolo
Pastinen, Tomi
Lu, Chao
Lewis, Peter W.
Garcia, Benjamin A.
Kleinman, Claudia L.
Jabado, Nada
Majewski, Jacek
author_facet Harutyunyan, Ashot S.
Krug, Brian
Chen, Haifen
Papillon-Cavanagh, Simon
Zeinieh, Michele
De Jay, Nicolas
Deshmukh, Shriya
Chen, Carol C. L.
Belle, Jad
Mikael, Leonie G.
Marchione, Dylan M.
Li, Rui
Nikbakht, Hamid
Hu, Bo
Cagnone, Gael
Cheung, Warren A.
Mohammadnia, Abdulshakour
Bechet, Denise
Faury, Damien
McConechy, Melissa K
Pathania, Manav
Jain, Siddhant U.
Ellezam, Benjamin
Weil, Alexander G.
Montpetit, Alexandre
Salomoni, Paolo
Pastinen, Tomi
Lu, Chao
Lewis, Peter W.
Garcia, Benjamin A.
Kleinman, Claudia L.
Jabado, Nada
Majewski, Jacek
author_sort Harutyunyan, Ashot S.
collection PubMed
description Lys-27-Met mutations in histone 3 genes (H3K27M) characterize a subgroup of deadly gliomas and decrease genome-wide H3K27 trimethylation. Here we use primary H3K27M tumor lines and isogenic CRISPR-edited controls to assess H3K27M effects in vitro and in vivo. We find that whereas H3K27me3 and H3K27me2 are normally deposited by PRC2 across broad regions, their deposition is severely reduced in H3.3K27M cells. H3K27me3 is unable to spread from large unmethylated CpG islands, while H3K27me2 can be deposited outside these PRC2 high-affinity sites but to levels corresponding to H3K27me3 deposition in wild-type cells. Our findings indicate that PRC2 recruitment and propagation on chromatin are seemingly unaffected by K27M, which mostly impairs spread of the repressive marks it catalyzes, especially H3K27me3. Genome-wide loss of H3K27me3 and me2 deposition has limited transcriptomic consequences, preferentially affecting lowly-expressed genes regulating neurogenesis. Removal of H3K27M restores H3K27me2/me3 spread, impairs cell proliferation, and completely abolishes their capacity to form tumors in mice.
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spelling pubmed-64250352019-03-21 H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis Harutyunyan, Ashot S. Krug, Brian Chen, Haifen Papillon-Cavanagh, Simon Zeinieh, Michele De Jay, Nicolas Deshmukh, Shriya Chen, Carol C. L. Belle, Jad Mikael, Leonie G. Marchione, Dylan M. Li, Rui Nikbakht, Hamid Hu, Bo Cagnone, Gael Cheung, Warren A. Mohammadnia, Abdulshakour Bechet, Denise Faury, Damien McConechy, Melissa K Pathania, Manav Jain, Siddhant U. Ellezam, Benjamin Weil, Alexander G. Montpetit, Alexandre Salomoni, Paolo Pastinen, Tomi Lu, Chao Lewis, Peter W. Garcia, Benjamin A. Kleinman, Claudia L. Jabado, Nada Majewski, Jacek Nat Commun Article Lys-27-Met mutations in histone 3 genes (H3K27M) characterize a subgroup of deadly gliomas and decrease genome-wide H3K27 trimethylation. Here we use primary H3K27M tumor lines and isogenic CRISPR-edited controls to assess H3K27M effects in vitro and in vivo. We find that whereas H3K27me3 and H3K27me2 are normally deposited by PRC2 across broad regions, their deposition is severely reduced in H3.3K27M cells. H3K27me3 is unable to spread from large unmethylated CpG islands, while H3K27me2 can be deposited outside these PRC2 high-affinity sites but to levels corresponding to H3K27me3 deposition in wild-type cells. Our findings indicate that PRC2 recruitment and propagation on chromatin are seemingly unaffected by K27M, which mostly impairs spread of the repressive marks it catalyzes, especially H3K27me3. Genome-wide loss of H3K27me3 and me2 deposition has limited transcriptomic consequences, preferentially affecting lowly-expressed genes regulating neurogenesis. Removal of H3K27M restores H3K27me2/me3 spread, impairs cell proliferation, and completely abolishes their capacity to form tumors in mice. Nature Publishing Group UK 2019-03-19 /pmc/articles/PMC6425035/ /pubmed/30890717 http://dx.doi.org/10.1038/s41467-019-09140-x Text en © The Author(s) 2019 Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Harutyunyan, Ashot S.
Krug, Brian
Chen, Haifen
Papillon-Cavanagh, Simon
Zeinieh, Michele
De Jay, Nicolas
Deshmukh, Shriya
Chen, Carol C. L.
Belle, Jad
Mikael, Leonie G.
Marchione, Dylan M.
Li, Rui
Nikbakht, Hamid
Hu, Bo
Cagnone, Gael
Cheung, Warren A.
Mohammadnia, Abdulshakour
Bechet, Denise
Faury, Damien
McConechy, Melissa K
Pathania, Manav
Jain, Siddhant U.
Ellezam, Benjamin
Weil, Alexander G.
Montpetit, Alexandre
Salomoni, Paolo
Pastinen, Tomi
Lu, Chao
Lewis, Peter W.
Garcia, Benjamin A.
Kleinman, Claudia L.
Jabado, Nada
Majewski, Jacek
H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis
title H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis
title_full H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis
title_fullStr H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis
title_full_unstemmed H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis
title_short H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis
title_sort h3k27m induces defective chromatin spread of prc2-mediated repressive h3k27me2/me3 and is essential for glioma tumorigenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425035/
https://www.ncbi.nlm.nih.gov/pubmed/30890717
http://dx.doi.org/10.1038/s41467-019-09140-x
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