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| Status |
Public on Oct 19, 2022 |
| Title |
The histone H3G34R mutation disrupts the epigenome via catalytic inactivation of the ASH1 H3K36 methyltransferase [RNA-seq] |
| Organism |
Neurospora crassa |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The recurrent mutation of histone variant H3.3 at glycine-34 (H3.3G34) defines a type of pediatric glioma. Characteristic changes to the epigenome associated with the disease are thought to be the consequence of altered methylation of the adjacent lysine-36 (K36) residue, but the complexity of this regulatory pathway in humans, combined with a multi-component disease etiology, has limited our understanding of how H3.3G34 mutations contribute to oncogenesis. Here we use Neurospora crassa to show that the most common mutation associated with this tumor, glycine to arginine (G34R), drives aberrant heterochromatin formation and abnormal growth by inhibiting the H3K36 methyltransferase ASH1. Inactivation of ASH1, either directly or with H3G34R, drives spurious intergenic DNA methylation, redistribution of H3K27 methylation, and derepression of silent genes. We provide evidence that these defects are largely due to aberrant activity of RNA polymerase II (RNAPII)-associated SET-2, and propose targeted SET-2 inhibition as a therapeutic strategy for H3.3G34R gliomas.
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| Overall design |
We analyzed gene expression changes in Neurospora crassa by poly-A+ mRNA-sequencing performed in duplicate. Five strains representing three genetic backgrounds (N5247, N5248 (H3G34R), N6777 (H3G34R; delta set-2), and N6266, N6267 (ash1(Y888F); delta set-2)) serve as test strains here. Wild-type controls used as reference and related, previously described, mutants are deposited at GSE82222 and GSE118495.
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| Contributor(s) |
Bicocca VT, Rountree MR, Ormsby T, Selker EU |
| Citation missing |
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| Submission date |
Jul 17, 2019 |
| Last update date |
Oct 22, 2022 |
| Contact name |
Elizabeth Toomey Wiles |
| E-mail(s) |
[email protected]
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| Organization name |
University of Oregon
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| Department |
Biology, Institute of Molecular Biology
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| Lab |
Selker
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| Street address |
1229 University of Oregon; 1318 Franklin Blvd.
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| City |
Eugene |
| State/province |
OR |
| ZIP/Postal code |
97403 |
| Country |
USA |
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| Platforms (2) |
| GPL20660 |
Illumina NextSeq 500 (Neurospora crassa) |
| GPL23150 |
Illumina HiSeq 4000 (Neurospora crassa) |
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| Samples (3) |
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| This SubSeries is part of SuperSeries: |
| GSE134452 |
The histone H3G34R mutation disrupts the epigenome via catalytic inactivation of the ASH1 H3K36 methyltransferase |
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| Relations |
| BioProject |
PRJNA555433 |
| SRA |
SRP215551 |
