The genome wide mapping of H3K9 and H3K23 acetylation in Moz+/+ and Moz-/- MOZ-TIF2 AML cells
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PROVIDER: PRJNA860935 | ENA |
REPOSITORIES: ENA
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Project description:Monocytic leukemia Zinc finger protein (MOZ) is a MYST-type acetyltransferase involved in chromosomal translocation in acute myelogenous leukemia (AML) and myelodysplastic syndrome. MOZ is established as essential for hematopoiesis; however, the role of MOZ in AML has not been addressed. We propose that MOZ is critical for AML development induced by MOZ-TIF2 fusions. Moz-deficient hematopoietic stem/progenitor cells (HSPCs) expressing MOZ-TIF2 could form colonies in vitro but could not induce AML in mice. By contrast, Moz was dispensable for colony formation by HOXA9-transduced cells and AML development caused by HOXA9 and MEIS1, suggesting a specific requirement for MOZ in AML induced by MOZ/MLL-fusions. Expression of the of Meis1, but not Hoxa9, was reduced in Moz-deficient MOZ-TIF2 AML cells. AML development induced by MOZ-TIF2 was rescued by introducing Meis1 into Moz-deficient cells carrying MOZ-TIF2. Meis1 deletion impaired MOZ-TIF2-mediated AML development. Active histone modifications were also severely reduced at the Meis1 locus in Moz-deficient MOZ-TIF2 AML cells. These results suggest that endogenous MOZ is critical for MOZ-fusion-induced AML development and maintains active chromatin signatures at target gene loci.
2022-07-24 | GSE208741 | GEO
Project description: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.
2024-07-03 | GSE260640 | GEO
Project description: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.
2024-07-03 | GSE260639 | GEO
Project description: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.
2024-07-03 | GSE260638 | GEO
Project description:Eradication of chemotherapy-resistant leukemia stem cells is expected to improve treatment outcomes in patients with acute myelogenous leukemia (AML). In a mouse model of AML expressing the MOZ-TIF2 fusion, we found that Ring1A and Ring1B, components of Polycomb repressive complex 1, play crucial roles in maintaining AML stem cells. Deletion of Ring1A and Ring1B (Ring1A/B) from MOZ-TIF2 AML cells diminished self-renewal capacity and induced the expression of numerous genes including Gli-similar 2 (Glis2). Overexpression of Glis2 caused MOZ-TIF2 AML cells to differentiate into mature cells, whereas Glis2 knockdown in Ring1A/B-deficient MOZ-TIF2 cells inhibited differentiation. Thus, Ring1A/B regulates and maintains AML stem cells in part by repressing Glis2 expression, which promotes their differentiation. These findings provide new insights into the mechanism of AML stem cell homeostasis and reveal novel targets for cancer stem cell therapy.
2017-01-06 | GSE93214 | GEO
Project description:Human acetyltransferases MOZ and MORF are implicated in chromosomal translocations associated with aggressive leukemias. Oncogenic translocations involve the far amino terminus of MOZ/MORF, the function of which remains unclear. Here, we identified and characterized two structured winged helix domains, WH1 and WH2, in MORF and MOZ. WHs bind DNA in a cooperative manner, with WH1 specifically recognizing unmethylated CpG sequences. Structural and genomic analyses show that the DNA binding function of WHs targets MORF/MOZ to gene promoters, stimulating transcription and H3K23 acetylation, and WH1 recruits oncogenic fusions to HOXA genes that trigger leukemogenesis. Cryo-EM, NMR, mass spectrometry and mutagenesis studies provide mechanistic insight into the DNA-binding mechanism, which includes the association of WH1 with the linker DNA and binding of WH2 to the dyad of the nucleosome, with the latter being further modulated by the neighboring domain DPF and autoacetylation of MORF. The discovery of WHs in MORF and MOZ and their DNA binding functions could open a new avenue in developing therapeutics to treat diseases associated with aberrant MOZ/MORF acetyltransferase activities.
2023-03-11 | PXD036192 | Pride
Project description:H3K9 acetylation was enriched in pluripotency genes in hESCs and in neural genes in neural progenitor cells Examination of H3K9 acetylation distributions in hESCs and neural progenitor cells
2015-03-11 | E-GEOD-66778 | biostudies-arrayexpress
Project description:SAGA member Ada2 is required for the majority of H3K9 acetylation in C. neoformans. To identify specific genomic loci that exhibit Ada2-dependent H3K9 acetylation, we performed ChIP-Seq against H3K9ac in wildtype and ada2Δ cells.
2012-01-01 | GSE32075 | GEO
Project description:SAGA member Ada2 is required for the majority of H3K9 acetylation in C. neoformans. To identify specific genomic loci that exhibit Ada2-dependent H3K9 acetylation, we performed ChIP-Seq against H3K9ac in wildtype and ada2Δ cells. ChIP-Seq was performed using antibodies for H3K9ac in KN99 wildtype cells and ada2Δ cells. Input and IPed DNA was collected in triplicate from each strain and sequenced on an Illumnina HiSeq 2000 flow cell producing 84 million reads. Due to the lack of quality scores, raw reads are omitted from the submission.
2012-01-01 | E-GEOD-32075 | biostudies-arrayexpress
Project description:Genome-wide maps of the H3K9 acetylation state in embryonic stem cells (ESCs) before and after treatment with low levels of the histone deacetylase (HDAC) inhibitor valproic acid (VPA).
2011-09-17 | GSE24211 | GEO