KAT6A Chimeras Forms a Self-Reinforcing Epigenetic Module with NURF and MLL/COMPASS in AML [ChIP-Seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1274025 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR33896901_1.fastq.gz | Fastqsanger.gz | |||
| SRR33896901_2.fastq.gz | Fastqsanger.gz | |||
| SRR33896902_1.fastq.gz | Fastqsanger.gz | |||
| SRR33896902_2.fastq.gz | Fastqsanger.gz |
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Project description:KAT6A-CBP (K/C) and KAT6A-P300 (K/P) fusions are recurrent genetic alterations in acute myeloid leukemia(AML) that are associated with poor prognosis. The large size of these fusion proteins has posed challenges in developing preclinical models, limiting mechanistic studies. To address this, we employed a domain-focused truncation strategy to generate de novo murine models of K/C and K/P fusions, which faithfully recapitulate the morphological, immunophenotypic, and transcriptomic features of KAT6A-rearranged AML. Genomic profiling revealed that KAT6A fusions preferentially localize to H3K4me2/3-marked regions and interact with the Nucleosome Remodeling Factor (NURF), a critical H3K4me2/3 reader. Disrupting NURF-chromatin interactions impaired K/C recruitment to target loci and disrupted MLL/COMPASS-mediated H3K4me2 deposition, thereby establishing an epigenetic regulatory module involving KAT6A chimeras, NURF, and MLL/COMPASS. Concurrently, CBP/P300 inhibition reduced histone acetylation, chromatin accessibility, and genomic targeting of the module. Therapeutically, NURF inhibition induced cell cycle arrest and suppressed leukemia proliferation, while CBP/P300 inhibition promoted leukemia differentiation. Both strategies demonstrated promising efficacy in K/C murine models, with superior effects observed with combined NURF and CBP/P300 inhibition. These findings uncover a self-reinforcing epigenetic module centered on histone reader proteins and modifying enzymes, providing mechanistic insights into KAT6A-rearranged AML and identifying promising combinatorial therapeutic vulnerabilities.
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Project description:KAT6A-CBP (K/C) and KAT6A-P300 (K/P) fusions are recurrent genetic alterations in acute myeloid leukemia(AML) that are associated with poor prognosis. The large size of these fusion proteins has posed challenges in developing preclinical models, limiting mechanistic studies. To address this, we employed a domain-focused truncation strategy to generate de novo murine models of K/C and K/P fusions, which faithfully recapitulate the morphological, immunophenotypic, and transcriptomic features of KAT6A-rearranged AML. Genomic profiling revealed that KAT6A fusions preferentially localize to H3K4me2/3-marked regions and interact with the Nucleosome Remodeling Factor (NURF), a critical H3K4me2/3 reader. Disrupting NURF-chromatin interactions impaired K/C recruitment to target loci and disrupted MLL/COMPASS-mediated H3K4me2 deposition, thereby establishing an epigenetic regulatory module involving KAT6A chimeras, NURF, and MLL/COMPASS. Concurrently, CBP/P300 inhibition reduced histone acetylation, chromatin accessibility, and genomic targeting of the module. Therapeutically, NURF inhibition induced cell cycle arrest and suppressed leukemia proliferation, while CBP/P300 inhibition promoted leukemia differentiation. Both strategies demonstrated promising efficacy in K/C murine models, with superior effects observed with combined NURF and CBP/P300 inhibition. These findings uncover a self-reinforcing epigenetic module centered on histone reader proteins and modifying enzymes, providing mechanistic insights into KAT6A-rearranged AML and identifying promising combinatorial therapeutic vulnerabilities.
2025-06-24 | GSE299382 | GEO
Project description:KAT6A-CBP (K/C) and KAT6A-P300 (K/P) fusions are recurrent genetic alterations in acute myeloid leukemia(AML) that are associated with poor prognosis. The large size of these fusion proteins has posed challenges in developing preclinical models, limiting mechanistic studies. To address this, we employed a domain-focused truncation strategy to generate de novo murine models of K/C and K/P fusions, which faithfully recapitulate the morphological, immunophenotypic, and transcriptomic features of KAT6A-rearranged AML. Genomic profiling revealed that KAT6A fusions preferentially localize to H3K4me2/3-marked regions and interact with the Nucleosome Remodeling Factor (NURF), a critical H3K4me2/3 reader. Disrupting NURF-chromatin interactions impaired K/C recruitment to target loci and disrupted MLL/COMPASS-mediated H3K4me2 deposition, thereby establishing an epigenetic regulatory module involving KAT6A chimeras, NURF, and MLL/COMPASS. Concurrently, CBP/P300 inhibition reduced histone acetylation, chromatin accessibility, and genomic targeting of the module. Therapeutically, NURF inhibition induced cell cycle arrest and suppressed leukemia proliferation, while CBP/P300 inhibition promoted leukemia differentiation. Both strategies demonstrated promising efficacy in K/C murine models, with superior effects observed with combined NURF and CBP/P300 inhibition. These findings uncover a self-reinforcing epigenetic module centered on histone reader proteins and modifying enzymes, providing mechanistic insights into KAT6A-rearranged AML and identifying promising combinatorial therapeutic vulnerabilities.
2025-06-24 | GSE299380 | GEO
Project description:KAT6A-CBP (K/C) and KAT6A-P300 (K/P) fusions are recurrent genetic alterations in acute myeloid leukemia(AML) that are associated with poor prognosis. The large size of these fusion proteins has posed challenges in developing preclinical models, limiting mechanistic studies. To address this, we employed a domain-focused truncation strategy to generate de novo murine models of K/C and K/P fusions, which faithfully recapitulate the morphological, immunophenotypic, and transcriptomic features of KAT6A-rearranged AML. Genomic profiling revealed that KAT6A fusions preferentially localize to H3K4me2/3-marked regions and interact with the Nucleosome Remodeling Factor (NURF), a critical H3K4me2/3 reader. Disrupting NURF-chromatin interactions impaired K/C recruitment to target loci and disrupted MLL/COMPASS-mediated H3K4me2 deposition, thereby establishing an epigenetic regulatory module involving KAT6A chimeras, NURF, and MLL/COMPASS. Concurrently, CBP/P300 inhibition reduced histone acetylation, chromatin accessibility, and genomic targeting of the module. Therapeutically, NURF inhibition induced cell cycle arrest and suppressed leukemia proliferation, while CBP/P300 inhibition promoted leukemia differentiation. Both strategies demonstrated promising efficacy in K/C murine models, with superior effects observed with combined NURF and CBP/P300 inhibition. These findings uncover a self-reinforcing epigenetic module centered on histone reader proteins and modifying enzymes, providing mechanistic insights into KAT6A-rearranged AML and identifying promising combinatorial therapeutic vulnerabilities.
2025-06-24 | GSE299381 | GEO
Project description:KAT6A-CBP (K/C) and KAT6A-P300 (K/P) fusions are recurrent genetic alterations in acute myeloid leukemia(AML) that are associated with poor prognosis. The large size of these fusion proteins has posed challenges in developing preclinical models, limiting mechanistic studies. To address this, we employed a domain-focused truncation strategy to generate de novo murine models of K/C and K/P fusions, which faithfully recapitulate the morphological, immunophenotypic, and transcriptomic features of KAT6A-rearranged AML. Genomic profiling revealed that KAT6A fusions preferentially localize to H3K4me2/3-marked regions and interact with the Nucleosome Remodeling Factor (NURF), a critical H3K4me2/3 reader. Disrupting NURF-chromatin interactions impaired K/C recruitment to target loci and disrupted MLL/COMPASS-mediated H3K4me2 deposition, thereby establishing an epigenetic regulatory module involving KAT6A chimeras, NURF, and MLL/COMPASS. Concurrently, CBP/P300 inhibition reduced histone acetylation, chromatin accessibility, and genomic targeting of the module. Therapeutically, NURF inhibition induced cell cycle arrest and suppressed leukemia proliferation, while CBP/P300 inhibition promoted leukemia differentiation. Both strategies demonstrated promising efficacy in K/C murine models, with superior effects observed with combined NURF and CBP/P300 inhibition. These findings uncover a self-reinforcing epigenetic module centered on histone reader proteins and modifying enzymes, providing mechanistic insights into KAT6A-rearranged AML and identifying promising combinatorial therapeutic vulnerabilities.
2025-06-24 | GSE299379 | GEO
Project description:KAT6A Chimeras Forms a Self-Reinforcing Epigenetic Module with NURF and MLL/COMPASS in AML [ChIPMNase]
| PRJNA1274026 | ENA
Project description:KAT6A Chimeras Forms a Self-Reinforcing Epigenetic Module with NURF and MLL/COMPASS in AML [ATAC-Seq]
| PRJNA1274027 | ENA
Project description:KAT6A Chimeras Forms a Self-Reinforcing Epigenetic Module with NURF and MLL/COMPASS in AML [RNA-Seq]
| PRJNA1274028 | ENA
Project description:KAT6A Chimeras Forms a Self-Reinforcing Epigenetic Module with NURF and MLL/COMPASS in AML [CUT&Run]
| PRJNA1274031 | ENA
Project description:The lysine acetyltransferase KAT6A (MOZ, MYST3) belongs to the MYST family of chromatin regulators, facilitating histone acetylation. Dysregulation of KAT6A has been implicated in developmental syndromes and the onset of acute myeloid leukemia (AML). Previous work suggests that KAT6A is recruited to its genomic targets by a combinatorial function of histone binding PHD fingers, transcription factors and chromatin binding interaction partners. Here, we demonstrated that a winged helix domain at the N-terminus of KAT6A specifically interacts with unmethylated CpG motifs. This DNA binding function leads to the association of KAT6A to unmethylated CpG islands (CGIs) genome wide. Mutation of the essential amino acids completely abrogates the enrichment of KAT6A at CGIs. Overexpression of a KAT6A WH1 mutant has a dominant negative effect on H3K9 histone acetylation, which is comparable to the effects upon overexpression of a KAT6A HAT domain mutant. Taken together, our work revealed a previously unrecognized chromatin recruitment mechanism of KAT6A, offering a new perspective on the role of KAT6A in gene regulation and human diseases
2023-01-14 | PXD034833 | Pride