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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE206274 | GEO | 2022/12/20

REPOSITORIES: GEO

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The 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 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.

| S-EPMC9881136 | biostudies-literature

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

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

2022-12-20 | GSE206273 | GEO

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

2022-12-20 | GSE206272 | GEO

MORF and MOZ acetyltransferases target unmethylated CpG islands through the winged helix domain.

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 (WH) 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 CpG-containing linker DNA and binding of WH2 to the dyad of the nucleosome. The discovery of WHs in MORF and MOZ and their DNA binding functions could open an avenue in developing therapeutics to treat diseases associated with aberrant MOZ/MORF acetyltransferase activities.

| S-EPMC9908889 | biostudies-literature

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

Project description:The histone acetyltransferase KAT6A is recruited to unmethylated CpG islands via a DNA binding winged helix domain

| PRJNA849937 | ENA

MORF and MOZ acetyltransferases target unmethylated CpG islands through the winged helix domain

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

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

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

| PRJNA849946 | ENA

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

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

| PRJNA849940 | ENA

The winged helix domain of MORF binds CpG islands and the TAZ2 domain of p300.

Project description:Acetylation of histones by lysine acetyltransferases (KATs) provides a fundamental mechanism by which chromatin structure and transcriptional programs are regulated. Here, we describe a dual binding activity of the first winged helix domain of human MORF KAT (MORFWH1) that recognizes the TAZ2 domain of p300 KAT (p300TAZ2) and CpG rich DNA sequences. Structural and biochemical studies identified distinct DNA and p300TAZ2 binding sites, allowing MORFWH1 to independently engage either ligand. Genomic data show that MORF/MOZWH1 colocalizes with H3K18ac, a product of enzymatic activity of p300, on CpG rich promoters of target genes. Our findings suggest a functional cooperation of MORF and p300 KATs in transcriptional regulation.

| S-EPMC10946326 | biostudies-literature

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