Mutant EZH2 alters the epigenetic network and increases epigenetic heterogeneity in B cell lymphoma.
Diffuse large B cell lymphomas and follicular lymphomas show recurrent mutations in epigenetic regulators; among these are loss-of-function mutations in KMT2D and gain-of-function mutations in EZH2. To systematically explore the effects of these mutations on the wiring of the epigenetic network, we...
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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2025-06-01
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| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.3003191 |
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| author | Ofir Griess Noa Furth Nofar Harpaz Nicoletta Di Bernardo Tomer-Meir Salame Bareket Dassa Ioannis Karagiannidis Yusuke Isshiki Menachem Gross Ari M Melnick Wendy Béguelin Guy Ron Efrat Shema |
| author_facet | Ofir Griess Noa Furth Nofar Harpaz Nicoletta Di Bernardo Tomer-Meir Salame Bareket Dassa Ioannis Karagiannidis Yusuke Isshiki Menachem Gross Ari M Melnick Wendy Béguelin Guy Ron Efrat Shema |
| author_sort | Ofir Griess |
| collection | DOAJ |
| description | Diffuse large B cell lymphomas and follicular lymphomas show recurrent mutations in epigenetic regulators; among these are loss-of-function mutations in KMT2D and gain-of-function mutations in EZH2. To systematically explore the effects of these mutations on the wiring of the epigenetic network, we applied a single-cell approach to probe a wide array of histone modifications. We show that mutant-EZH2 elicits extensive effects on the epigenome of lymphomas, beyond alterations to H3K27 methylations, and is epistatic over KMT2D mutations. Utilizing the single-cell data, we present computational methods to measure epigenetic heterogeneity. We identify an unexpected characteristic of mutant-EZH2, but not KMT2D, in increasing heterogeneity, shedding light on a novel oncogenic mechanism mediated by this mutation. Finally, we present tools to reconstruct known interactions within the epigenetic network, as well as reveal potential novel cross talk between various modifications, supported by functional perturbations. Our work highlights novel roles for mutant-EZH2 in lymphomagenesis and establishes new concepts for measuring epigenetic heterogeneity and intra-chromatin connectivity in cancer cells. |
| format | Article |
| id | doaj-art-15f7583d3cbf4310a01e4792b2539c18 |
| institution | OA Journals |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj-art-15f7583d3cbf4310a01e4792b2539c182025-08-20T02:35:44ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852025-06-01236e300319110.1371/journal.pbio.3003191Mutant EZH2 alters the epigenetic network and increases epigenetic heterogeneity in B cell lymphoma.Ofir GriessNoa FurthNofar HarpazNicoletta Di BernardoTomer-Meir SalameBareket DassaIoannis KaragiannidisYusuke IsshikiMenachem GrossAri M MelnickWendy BéguelinGuy RonEfrat ShemaDiffuse large B cell lymphomas and follicular lymphomas show recurrent mutations in epigenetic regulators; among these are loss-of-function mutations in KMT2D and gain-of-function mutations in EZH2. To systematically explore the effects of these mutations on the wiring of the epigenetic network, we applied a single-cell approach to probe a wide array of histone modifications. We show that mutant-EZH2 elicits extensive effects on the epigenome of lymphomas, beyond alterations to H3K27 methylations, and is epistatic over KMT2D mutations. Utilizing the single-cell data, we present computational methods to measure epigenetic heterogeneity. We identify an unexpected characteristic of mutant-EZH2, but not KMT2D, in increasing heterogeneity, shedding light on a novel oncogenic mechanism mediated by this mutation. Finally, we present tools to reconstruct known interactions within the epigenetic network, as well as reveal potential novel cross talk between various modifications, supported by functional perturbations. Our work highlights novel roles for mutant-EZH2 in lymphomagenesis and establishes new concepts for measuring epigenetic heterogeneity and intra-chromatin connectivity in cancer cells.https://doi.org/10.1371/journal.pbio.3003191 |
| spellingShingle | Ofir Griess Noa Furth Nofar Harpaz Nicoletta Di Bernardo Tomer-Meir Salame Bareket Dassa Ioannis Karagiannidis Yusuke Isshiki Menachem Gross Ari M Melnick Wendy Béguelin Guy Ron Efrat Shema Mutant EZH2 alters the epigenetic network and increases epigenetic heterogeneity in B cell lymphoma. PLoS Biology |
| title | Mutant EZH2 alters the epigenetic network and increases epigenetic heterogeneity in B cell lymphoma. |
| title_full | Mutant EZH2 alters the epigenetic network and increases epigenetic heterogeneity in B cell lymphoma. |
| title_fullStr | Mutant EZH2 alters the epigenetic network and increases epigenetic heterogeneity in B cell lymphoma. |
| title_full_unstemmed | Mutant EZH2 alters the epigenetic network and increases epigenetic heterogeneity in B cell lymphoma. |
| title_short | Mutant EZH2 alters the epigenetic network and increases epigenetic heterogeneity in B cell lymphoma. |
| title_sort | mutant ezh2 alters the epigenetic network and increases epigenetic heterogeneity in b cell lymphoma |
| url | https://doi.org/10.1371/journal.pbio.3003191 |
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