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The lysine acetyltransferase KAT6A epigenetically facilitates glucose metabolic programming and CD4+ T-cell responses in autoimmunity

ABSTRACT: The lysine acetyltransferase KAT6A epigenetically facilitates glucose metabolic programming and CD4+ T-cell responses in autoimmunity

PROVIDER: PRJNA1006399 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25679705_1.fastq.gz	Fastqsanger.gz
	SRR25679705_2.fastq.gz	Fastqsanger.gz
	SRR25679706_1.fastq.gz	Fastqsanger.gz
	SRR25679706_2.fastq.gz	Fastqsanger.gz
	SRR25679707_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

The lysine acetyltransferase KAT6A epigenetically facilitates glucose metabolic programming and CD4+ T-cell responses in autoimmunity

Project description:Epigenetic programs are pivotal regulators of effector CD4+ T cells and determine the fate of many autoimmune disorders. Here, we show that the acetyltransferase KAT6A acts as a novel regulator of glucose metabolism that is required for the proliferation and effector functions of CD4+ T cells in autoimmunity. Clinical analysis shows that KAT6A in CD4+ T cells is linked to the progression of autoimmune Sjogren’s syndrome (SS) . Conditional knockout of KAT6A inhibits the proliferation and Th1/Th17 effector functions of CD4+ T cells both in vitro and that KAT6A-cKO CD4+T cells are less susceptible to induce adjuvant-immunized experimental autoimmune encephalomyelitis (EAE), autoimmune colitis and experimental SS. Combination of metabolomic, epigenetic and transcriptomic analyses show that KAT6A maintains abundant acetylation of H3K9ac and H3K27ac sites of several glycolytic genes, which in turn disrupts the transcriptional activation of MYC and HIF-1α, and potentiates the metabolic programming of glycolysis through its enzymatic amino acid points. Treatment with KAT6A small-molecule inhibitors in various autoimmune mice models shows high therapeutic value for targeting KAT6A to the treatment of autoimmune disorders. Our study reveals a critical role for KAT6A in autoimmunity via the epigenetic modification of glucose metabolic reprogramming and the effector response of CD4+ T cells.

2023-12-09 | GSE241099 | GEO

The histone acetyltransferase KAT6A is recruited to unmethylated CpG islands via a DNA-binding winged helix domainThe histone acetyltransferase KAT6A is recruited to unmethylated CpG islands via a DNA-binding winged helix domain

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

RNA sequeqncing data of Kat6a–/–, Kat6a+/– and Kat6a+/+ E12.5 dorsal telencephalon and of Kat6a+/– and Kat6a+/+ E16.5 cortical neurons

Project description:Mutation of one allele of the KAT6A gene encoding the histone acetyltransferase KAT6A (MOZ, MYST3) causes Arboleda-Tham-Syndrome (ARTHS), which is characterised by developmental delay, cognitive impairment and autism-like behaviours. We used mice to examine the effects of Kat6a mutations on gene expression in the develping cerebral cortex and cortical neurons. We examined the effects of homozygous and heterozygous loss of Kat6a on gene expression in the E12.5 dorsal telecencephalon, the embryonic precursor of the cerebral cortex, and the effects of heterozygous loss of Kat6a on gene expression in foetal cortical neurons.

2026-02-03 | GSE304794 | GEO

The histone acetyltransferase KAT6A is recruited to unmethylated CpG islands via a DNA binding winged helix domain [RNA-seq]

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.

2022-12-20 | GSE206273 | GEO

The histone acetyltransferase KAT6A is recruited to unmethylated CpG islands via a DNA binding winged helix domain [ChIP-seq]

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.

2022-12-20 | GSE206272 | GEO

Immunoprecipitation and mass spectrometry (IP-MS) on KAT6A chimeras

Project description:Despite KAT6A chimeras potent oncogenic activity, the mechanisms by which KAT6A fusion proteins achieve genomic specificity and drive leukemogenesis remain poorly understood. Previous studies suggest that the leukemogenic potential of KAT6A-TIF2 depends on its chromatin-binding ability rather than its histone acetyltransferase (HAT) activity, with oncogenicity further amplified by CBP recruitment through its fusion partners. The winged helix domain (WH1) of KAT6A can bind unmethylated CpG islands and interact with P300/CBP via the TAZ2 domain. However, the widespread presence of unmethylated CpG islands across the genome does not fully explain the genomic specificity of KAT6A-CBP (K/C) and KAT6A-P300 (K/P) fusions, leaving key mechanistic gaps unexplored. To uncover protein interactions underlying these genomic associations, we performed immunoprecipitation and mass spectrometry (IP-MS) on KAT6A N-terminus and chimeras. Mass spectrometry analysis was performed to identify the core components of the KAT6A complex and the interacting proteins of KAT6A.

2025-08-08 | PXD061491 | Pride

KAT6A acetylation mediates metabolic adaptation to growth and mitochondrial metabolism through AMPK

Project description:We have previously demonstrated that a ketogenic diet alleviates cardiac pathology under high blood pressure. Here we show that lysine acetyltransferase 6A (KAT6A) is acetylated in the hearts of mice fed a ketogenic diet under hypertension, which enhances its interaction with AMPK regulatory subunits. RNA-sequencing analysis demonstrated that the KAT6A-K815Q acetylation-mimetic mutant stimulates AMPK signaling in cardiomyocytes. Moreover, the KAT6A-K815Q acetylation-mimetic mutant mitigated phenylephrine-induced mitochondrial dysfunction and cardiomyocyte hypertrophy via AMPK activation in vitro.

2025-12-02 | GSE286926 | GEO

Interaction proteins with KAT6A

Project description:Lysine acetyltransferases (KATs) catalyze the transfer of acetyl groups from acetyl-CoA to lysine residues. Our proteomic analysis revealed that KAT6A is acetylated at lysine 815 (K815), corresponding to mouse K816, in the hearts of mice fed a ketogenic diet under high blood pressure. To identify changes in KAT6A interaction partners by K815 acetylation in cardiomyocytes, we performed LC-MS/MS proteomics. We transfected adenovirus-carrying FLAG-KAT6A-wild type (WT, Control (Ctrl)), -K815R (an acetylation resistant mutant, KR), and -K815Q (an acetylation mimetic mutant, KQ) into cardiomyocytes for 2 days. Adenovirus-carrying FLAG was used as a control. KAT6A was immunoprecipitated with anti-FLAG affinity beads, followed by washing, competitive elution with 3x FLAG peptides, and separation by SDS-PAGE.

2025-11-03 | PXD059838 | Pride

RNA sequeqncing data of Kat6a–/–, Kat6a+/– and Kat6a+/+ E12.5 dorsal telencephalon and of Kat6a+/– and Kat6a+/+ E16.5 cortical neurons

Project description:RNA sequeqncing data of Kat6a–/–, Kat6a+/– and Kat6a+/+ E12.5 dorsal telencephalon and of Kat6a+/– and Kat6a+/+ E16.5 cortical neurons

| PRJNA1302771 | ENA

KAT6A acetylation of SMAD3 regulates tumor metastasis in triple-negative breast cancer

Project description:Aberrant SMAD3 activation has been implicated as a driving event in cancer metastasis. However, the drivers of SMAD3 activation are poorly defined. Here, we identify SMAD3 as a non-histone substrate of lysine acetyltransferase 6A (KAT6A). The acetylation of SMAD3 at K20 and K117 by KAT6A with promotes SMAD3 association with oncogenic H3K23ac reader TRIM24 and upregulation of immune response-related cytokines. This event in turn leads to enhanced myeloid-derived suppressor cell (MDSC) recruitment and triple-negative breast cancer (TNBC) metastasis. Inhibiting KAT6A in combination with anti-PD-L1 therapy in treating breast cancer xenograft-bearing animals markedly attenuates TNBC metastasis and provides a significant survival benefit. Thus, our work presents an KAT6A acetylation-dependent regulatory mechanism governing SMAD3 oncogenic function and provides insight into how targeting an epigenetic factor with immunotherapies enhances the anti-metastasis efficacy.

2021-11-03 | GSE171230 | GEO

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