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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jul 03, 2024 |
| Title |
A MOZ-TIF2 leukemic mouse model displays KAT6 inhibitor-sensitive H3K23 propionylation and dysregulation of a set of highly active developmental genes [Cut&Run] |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Aberrant regulation of chromatin modifiers is a common occurrence across many cancer types, and a key priority is to determine how specific alteration of these proteins, often enzymes, can be targeted therapeutically. MOZ, a histone acyltransferase, is recurrently fused to coactivators CBP, p300, and TIF2 in cases of Acute Myeloid Leukemia (AML). Using either pharmacological inhibition or targeted protein degradation in a mouse model for MOZ-TIF2-driven leukemia, we show that KAT6 (MOZ/MORF) enzymatic activity and the MOZ-TIF2 protein are necessary for indefinite proliferation in cell culture. Interestingly, MOZ enzymatic activity is selectively required in MOZ-TIF2 cells, as murine MLL-AF9 leukemic cells show no sensitivity to the WM-1119 MOZ inhibitor. MOZ-TIF2 directly regulates a small subset of genes encoding developmental transcription factors, augmenting their high expression. Transcription levels of these genes positively correlate with enrichment of histone H3 propionylation at lysine 23 (H3K23pr), a recently appreciated histone acylation associated with gene activation. Unexpectedly, we also show that MOZ-TIF2 and MLL-AF9 regulate transcription of largely non-overlapping gene sets, and their cellular models exhibit distinct sensitivities to multiple small molecule inhibitors directed against AML pathways. This is despite the shared genetic pathways of wild-type MOZ and MLL. Overall, our data provide insight into how aberrant regulation of MOZ contributes to leukemogenesis. We anticipate these experiments will inform future work identifying targeted therapies in the treatment of AML and other diseases involving MOZ-induced transcriptional dysregulation.
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| Overall design |
Cut&Run DNA sequencing against HA or IgG in FKBPV12-HA-MOZ-TIF2 LSK from mouse bone marrow treated with DMSO or 500 nM dTAG13 for 2 hours
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| Contributor(s) |
Smolko A, Kuroda M |
| Citation(s) |
38889153 |
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| Submission date |
Feb 29, 2024 |
| Last update date |
Jul 04, 2024 |
| Contact name |
Mitzi I Kuroda |
| E-mail(s) |
mkuroda@genetics.med.harvard.edu
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| Organization name |
Brigham and Women's Hospital/Harvard Medical School
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| Department |
Genetics
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| Lab |
Mitzi Kuroda
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| Street address |
77 Avenue Louis Pasteur
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| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02115 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (8)
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| GSM8121397 |
FKBPV12-HA-MOZ-TIF2 LSK, HA DMSO, rep 1 |
| GSM8121398 |
FKBPV12-HA-MOZ-TIF2 LSK, HA DMSO, rep 2 |
| GSM8121399 |
FKBPV12-HA-MOZ-TIF2 LSK, HA dTAG13, rep 1 |
| GSM8121400 |
FKBPV12-HA-MOZ-TIF2 LSK, HA dTAG13, rep 2 |
| GSM8121401 |
FKBPV12-HA-MOZ-TIF2 LSK, IgG DMSO, rep 1 |
| GSM8121402 |
FKBPV12-HA-MOZ-TIF2 LSK, IgG DMSO, rep 2 |
| GSM8121403 |
FKBPV12-HA-MOZ-TIF2 LSK, IgG dTAG13, rep 1 |
| GSM8121404 |
FKBPV12-HA-MOZ-TIF2 LSK, IgG dTAG13, rep 2 |
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| Relations |
| BioProject |
PRJNA1082388 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE260640_RAW.tar |
1.4 Gb |
(http)(custom) |
TAR (of BW) |
SRA Run Selector |
| Raw data are available in SRA |
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