Inhibition of the MYST histone acetyltransferases KAT6A/B arrests lymphoma progression
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ABSTRACT:
PROVIDER: PRJNA422902 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6387440_1.fastq.gz | Fastqsanger.gz | |||
| SRR6387440_2.fastq.gz | Fastqsanger.gz | |||
| SRR6387441_1.fastq.gz | Fastqsanger.gz | |||
| SRR6387441_2.fastq.gz | Fastqsanger.gz | |||
| SRR6387432_1.fastq.gz | Fastqsanger.gz |
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Project description:Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function. The MYST family of KATs (KAT5-8) includes the oncogenes KAT6A (MOZ) and KAT6B (MORF/QKF). KAT6A has essential roles in normal hematopoietic stem cells and is the target of recurrent chromosomal translocations, causing acute myeloid leukemia. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers. KAT6A suppresses cellular senescence via regulation of suppressors of the CDKN2A locus, a function that requires its KAT activity. Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days. These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. We have produced a series of highly potent, selective inhibitors of KAT6A/B including WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible acetyl-CoA competitors and inhibit MYST-catalyzed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF dependent and accompanied by gene expression changes typical of loss of KAT6A function. We anticipate that this class of inhibitors will be useful in accelerating development of therapeutics targeting gene transcription regulated by histone acetylation. We show that WM-1119 arrests lymphoma progression in mice. The B cell lymphoma cell line, EMRK1184, was isolated from Eμ-Myc transgenic mice, which are mice with a tumor resulting from the expression of cMyc under the control of the IgH enhancer. EMRK1184 expresses the Cdnk2a locus-encoded ARF and wild type p53. Treatment with WM-1119 inhibited the proliferation of the EMRK1184 lymphoma cells in vitro. RNA-seq and Western blot analysis showed that WM-1119 treatment resulted in increased levels of Cdkn2a and Cdkn2b mRNA and P16INK4a and p19ARF protein, as well as a delayed increase in Cdkn1a mRNA. The data here present RNA-seq profiling of EMRK1184 lymphomas treated with either WM-1119 or a control.
2018-08-03 | GSE114962 | GEO
Project description:Acetylation of histones by lysine acetyltransferases (KATs) is essential for transcriptional regulation of gene expression. The MYST family of KATs (KAT5-8) includes the oncogenes KAT6A (MOZ) and KAT6B (MORF/QKF). KAT6A has key roles in promoting cell proliferation through transcriptional activation of negative regulators of the Cdkn2a locus, which encode the tumor suppressors INK4A and ARF. To examine the loss of KAT6A function, mouse embryonic fibroblasts (MEFs) were isolated from E13.5 Kat6a+/+ and Kat6a–/– embryos and RNA-seq profiling was performed.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2018-08-03 | GSE108244 | GEO
Project description:Acetylation of histones by lysine acetyltransferases (KATs) is essential for transcriptional regulation of gene expression. The MYST family of KATs (KAT5-8) includes the oncogenes KAT6A (MOZ) and KAT6B (MORF/QKF). KAT6A has key roles in promoting cell proliferation through transcriptional activation of negative regulators of the Cdkn2a locus, which encode the tumor suppressors INK4A and ARF. We produced a series of highly potent, selective inhibitors of KAT6A/B including WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible acetyl-CoA competitors. WM-8014 and WM-1119 inhibit MYST-catalyzed histone acetylation, thereby inducing cell cycle exit and cellular senescence, without causing DNA damage. The data here examine the transcriptional effects of WM-8014. Mouse embryonic fibroblasts (MEFs) were treated with either WM-8014 or with WM-2474, an inactive control, for either 96 hours or 240 hours and RNA-seq profiling was undertaken.
2018-08-03 | GSE108243 | GEO
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
Project description:Histone acetyltransferases (HAT) assemble into multisubunit complexes in order to target distinct lysine residues on nucleosomal histones. Here, we characterize native HAT complexes assembled by the BRPF-family of scaffold proteins. Their PHD-ZnKnuckle-PHD domain is essential for binding chromatin and restricted to unmethylated H3K4, a specificity that is reversed by the associated ING subunit. Native BRPF1 complexes can contain either MOZ/MORF or HBO1 as catalytic acetyltransferase subunit. Interestingly, while the previously reported HBO1 complexes containing JADE scaffold proteins target histone H4, the HBO1-BRPF1 complex acetylates only H3 in chromatin. We mapped a small region at the N-terminus of scaffold proteins responsible for histone tail selection on chromatin. Thus, alternate choice of subunits associated with HBO1 can switch its specificity from H4 to H3 tails, highlighting a crucial new role of associated subunits within HAT complexes, previously thought to be intrinsic to the catalytic subunit. Genome-wide mapping of MYST acetyltransferases subunits and H3K4me3 histone mark in RKO cells.
2013-10-09 | E-GEOD-47190 | biostudies-arrayexpress
Project description:Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function. The MYST family of KATs (KAT5-8) includes the oncogenes KAT6A (MOZ) and KAT6B (MORF/QKF). KAT6A has essential roles in normal hematopoietic stem cells and is the target of recurrent chromosomal translocations, causing acute myeloid leukemia. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers. KAT6A suppresses cellular senescence via regulation of suppressors of the CDKN2A locus, a function that requires its KAT activity. Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days. These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. We have produced a series of highly potent, selective inhibitors of KAT6A/B including WM-8014 and WM-1119, which we anticipate will be useul in accelerating development of therapeutics. For comparison purposes, we also generated an inactive analogue WM-2474 as a control treatment. The data here focus on WM-2474 and present RNA-seq profiling of mouse embryonic fibroblasts (MEFs) treated with either WM-2472 or DMSO.
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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 demonstrate that a winged helix (WH) domain at the very N-terminus of KAT6A specifically interacts with unmethylated CpG motifs. This DNA binding function leads to the association of KAT6A with unmethylated CpG islands (CGIs) genome-wide. Mutation of the essential amino acids for DNA binding completely abrogates the enrichment of KAT6A at CGIs. In contrast, deletion of a second WH domain or the histone tail binding PHD fingers only subtly influences the binding of KAT6A to 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.
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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 demonstrate that a winged helix (WH) domain at the very N-terminus of KAT6A specifically interacts with unmethylated CpG motifs. This DNA binding function leads to the association of KAT6A with unmethylated CpG islands (CGIs) genome-wide. Mutation of the essential amino acids for DNA binding completely abrogates the enrichment of KAT6A at CGIs. In contrast, deletion of a second WH domain or the histone tail binding PHD fingers only subtly influences the binding of KAT6A to 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.
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