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| Status |
Public on May 01, 2024 |
| Title |
H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in paediatric high-grade glioma cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Diffuse intrinsic pontine gliomas (DIPG) are paediatric malignant gliomas developing in the brainstem, where resection is unattainable, leaving palliative radiotherapy as the major standard of care. Patients with DIPG have dismal prognosis of 9-12 months of survival and currently there is no effective therapy. Over 80% of DIPGs harbour a mutation in histone 3 (H3.3 or H3.1) resulting in a lysine to methionine substitution (H3K27M). H3K27M causes global epigenetic alterations (a loss of H3K27 trimethylation and an increase H3K27 acetylation) resulting in aberrant gene expression. To date, no therapeutic strategy exists to suppress the levels of oncogenic H3K27M. We show that pan-HDAC inhibitors (HDACi) lead to the temporary but significant reduction in the H3.3K27M protein (up to 80%) in multiple glioma cell lines expressing the H3.3K27M histone variant, without changes in the H3F3A mRNA expression. The H3.3K27M occupancy at the chromatin is greatly reduced upon HDACi (SB939) treatment, as shown by ChIPseq analysis. H3.3K27M loss is most striking at SB939-upregulated genes suggesting re-expression of repressed genes. Certain H3K27M-dependent genes become downregulated in response to SB939 treatment. We discover that the SB939-mediated loss of H3.3K27M is partially blocked by a lysosomal inhibitor chloroquine. Moreover, the loss of H3.3K27M is facilitated by co-occurrence of H2A.Z, as evidenced by the knock-down of H2A.Z histone isoforms. ChIPseq analysis confirms the occupancy of H3.3K27M and H2A.Z at the same SB939-inducible genes. Altogether, we provide new insight into disease-specific mechanism of HDAC inhibition and demonstrate pharmacological modulation of the oncogenic H3.3K27M protein levels. These findings open a new possibility to directly target the H3.3K27M oncohistone, which may be exploited in future therapies.
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| Overall design |
Comparative gene expression profiling analysis of RNA-seq and ChIP-seq data for DIPG H3.3K27M cells treated with DMSO (control) or SB9393 (HDACi).
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| Contributor(s) |
Leszczynska K, Mieczkowski J |
| Citation(s) |
38306270 |
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| Submission date |
May 11, 2023 |
| Last update date |
May 02, 2024 |
| Contact name |
Jakub Mieczkowski |
| E-mail(s) |
jmieczkowski@jmieczkowski.pl
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| Organization name |
Medical University of Gdansk
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| Street address |
Debinki 12
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| City |
Gdansk |
| ZIP/Postal code |
80-211 |
| Country |
Poland |
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| Platforms (2) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (47)
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| GSM7324883 |
Sample 4_SF7761, RNA-seq, SB939 |
| GSM7324884 |
Sample 5_DIPGXIII, RNA-seq, DMSO |
| GSM7324885 |
Sample 6_DIPGXIII, RNA-seq, SB939 |
| GSM7324886 |
Sample 7_DIPGXIII, RNA-seq, DMSO |
| GSM7324887 |
Sample 8_DIPGXIII, RNA-seq, SB939 |
| GSM7324888 |
Sample 9_SF7761, ChIP-seq H2A.Z, DMSO |
| GSM7324889 |
Sample 10_SF7761, ChIP-seq H2A.Z, SB939 |
| GSM7324890 |
Sample 11_SF7761, ChIP-seq H2A.Z, DMSO |
| GSM7324891 |
Sample 12_SF7761, ChIP-seq H2A.Z, SB939 |
| GSM7324892 |
Sample 13_DIPGXIII, ChIP-seq H2A.Z, DMSO |
| GSM7324893 |
Sample 14_DIPGXIII, ChIP-seq H2A.Z, SB939 |
| GSM7324894 |
Sample 15_DIPGXIII, ChIP-seq H2A.Z, DMSO |
| GSM7324895 |
Sample 16_DIPGXIII, ChIP-seq H2A.Z, SB939 |
| GSM7324896 |
Sample 17_SF7761, ChIP-seq H3.3, DMSO |
| GSM7324897 |
Sample 18_SF7761, ChIP-seq H3.3, SB939 |
| GSM7324898 |
Sample 19_SF7761, ChIP-seq H3.3, DMSO |
| GSM7324899 |
Sample 20_SF7761, ChIP-seq H3.3, SB939 |
| GSM7324900 |
Sample 21_DIPGXIII, ChIP-seq H3.3, DMSO |
| GSM7324901 |
Sample 22_DIPGXIII, ChIP-seq H3.3, SB939 |
| GSM7324902 |
Sample 23_DIPGXIII, ChIP-seq H3.3, DMSO |
| GSM7324903 |
Sample 24_DIPGXIII, ChIP-seq H3.3, SB939 |
| GSM7324904 |
Sample 25_SF7761, ChIP-seq H3.3K27M, DMSO |
| GSM7324905 |
Sample 26_SF7761, ChIP-seq H3.3K27M, SB939 |
| GSM7324906 |
Sample 27_SF7761, ChIP-seq H3.3K27M, DMSO |
| GSM7324907 |
Sample 28_SF7761, ChIP-seq H3.3K27M, SB939 |
| GSM7324908 |
Sample 29_DIPGXIII, ChIP-seq H3.3K27M, DMSO |
| GSM7324909 |
Sample 30_DIPGXIII, ChIP-seq H3.3K27M, SB939 |
| GSM7324910 |
Sample 31_DIPGXIII, ChIP-seq H3.3K27M, DMSO |
| GSM7324911 |
Sample 32_DIPGXIII, ChIP-seq H3.3K27M, SB939 |
| GSM7855167 |
DIPGXIII, RNA-seq, DMSO, replicate 1 |
| GSM7855168 |
DIPGXIII, RNA-seq, DMSO, replicate 2 |
| GSM7855169 |
DIPGXIII, RNA-seq, DMSO, replicate 3 |
| GSM7855170 |
DIPGXIII, RNA-seq, 3h after SB939, replicate 1 |
| GSM7855171 |
DIPGXIII, RNA-seq, 3h after SB939, replicate 2 |
| GSM7855172 |
DIPGXIII, RNA-seq, 3h after SB939, replicate 3 |
| GSM7855173 |
DIPGXIII, RNA-seq, 16h after SB939, replicate 1 |
| GSM7855174 |
DIPGXIII, RNA-seq, 16h after SB939, replicate 2 |
| GSM7855175 |
DIPGXIII, RNA-seq, 16h after SB939, replicate 3 |
| GSM7855176 |
DIPGXIII, RNA-seq, 48h after SB939, replicate 1 |
| GSM7855177 |
DIPGXIII, RNA-seq, 48h after SB939, replicate 2 |
| GSM7855178 |
DIPGXIII, RNA-seq, 48h after SB939, replicate 3 |
| GSM7855179 |
DIPGXIII, RNA-seq, 72h after SB939, replicate 1 |
| GSM7855180 |
DIPGXIII, RNA-seq, 72h after SB939, replicate 2 |
| GSM7855181 |
DIPGXIII, RNA-seq, 72h after SB939, replicate 3 |
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| Relations |
| BioProject |
PRJNA971530 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE232283_RAW.tar |
7.8 Gb |
(http)(custom) |
TAR (of WIG) |
| GSE232283_TPMs_RNAseq.tsv.gz |
1.7 Mb |
(ftp)(http) |
TSV |
| GSE232283_TPMs_TimeCourse_RNAseq.tsv.gz |
3.0 Mb |
(ftp)(http) |
TSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
| Processed data are available on Series record |
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