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Loss of PHF20 does not negatively affect deposition of H4K16 acetylation, but does impact the expression of MOF targets

ABSTRACT: Protein post-translational modifications transmit signals in part by creating binding sites for effector molecules. This is especially true in epigenetic pathways where histone tails are heavily modified, resulting in the recruitment of molecules that can affect transcription. One such molecule, plant homeodomain finger protein 20 (PHF20), uses a Tudor domain to read dimethyl-lysine residues and is a known component of the MOF histone acetyltransferase protein complex, suggesting it plays a role in the crosstalk between lysine methylation and histone acetylation. We sought to investigate the biological role of PHF20 by generating a knockout mouse. Without PHF20, mice die shortly after birth and display a wide variety of phenotypes within the skeletal and hematopoietic systems. Mechanistically, PHF20 is not required for maintaining the global H4K16 acetylation levels, but instead works downstream in transcriptional regulation of MOF target genes.

ORGANISM(S): Mus musculus

PROVIDER: GSE29306 | GEO | 2012/02/27

SECONDARY ACCESSION(S): PRJNA138641

REPOSITORIES: GEO

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Loss of PHF20 does not negatively affect deposition of H4K16 acetylation, but does impact the expression of MOF targets

Project description:Protein post-translational modifications transmit signals in part by creating binding sites for effector molecules. This is especially true in epigenetic pathways where histone tails are heavily modified, resulting in the recruitment of molecules that can affect transcription. One such molecule, plant homeodomain finger protein 20 (PHF20), uses a Tudor domain to read dimethyl-lysine residues and is a known component of the MOF histone acetyltransferase protein complex, suggesting it plays a role in the crosstalk between lysine methylation and histone acetylation. We sought to investigate the biological role of PHF20 by generating a knockout mouse. Without PHF20, mice die shortly after birth and display a wide variety of phenotypes within the skeletal and hematopoietic systems. Mechanistically, PHF20 is not required for maintaining the global H4K16 acetylation levels, but instead works downstream in transcriptional regulation of MOF target genes. ChIP sequencing of H4K16ace ChIP DNA from PHF20 knockout and wild type cells using Illumina Solexa Genome Analyzer II single end sequencing protocol.

2012-02-27 | E-GEOD-29306 | biostudies-arrayexpress

PHF20 readers link methylation of histone H3K4 and p53 with H4K16 acetylation

Project description:PHF20 is a core component of the lysine acetyltransferase complex MOF-NSL that produces the major epigenetic mark, H4K16ac, and is necessary for transcriptional regulation and DNA repair, however the role of PHF20 in the complex remains elusive. Here, we report on functional crosstalk between epigenetic readers of PHF20. We show that the PHF20 PHD finger recognizes dimethylated lysine 4 of histone H3 (H3K4me2) and represents first example of a native PHD reader selective for this modification. Biochemical and structural analyses illuminate the molecular mechanism underlying this function and explain the preference of Tudor2, another reader in PHF20, for dimethylated p53. Binding of the PHD finger to H3K4me2 is required for histone acetylation, accumulation of PHF20 at target genes, and transcriptional activation. Together, our findings establish a novel PHF20-mediated link between MOF HAT, p53 and H3K4me2-dependent cellular events and suggest a model for rapid spreading of H4K16ac-encriched open chromatin.

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G9a-Mediated Methylation of ERα Links the PHF20/MOF Histone Acetyltransferase Complex to Hormonal Gene Expression

Project description:The euchromatin histone methyltransferase 2 (EHMT2, aka G9a) methylates histone H3K9 to repress gene expression, but it also acts as a coactivator for some nuclear receptors. The molecular mechanisms underlying this activation remain elusive. Here we show that G9a functions as a bona fide coactivator of the endogenous estrogen receptor α (ERα) in breast cancer cells in a histone methylation-independent manner. G9a dimethylates ERα protein at lysine 235 both in vitro and in cells. Dimethylation of ERαK235 (ERαK235me2) is recognized by the Tudor domain of PHF20, which in turn recruits the MOF histone acetyltransferase (HAT) complex to ERα target gene promoters to deposit histone H4K16 acetylation promoting active transcription. Together, our in vitro and in vivo data establish the molecular mechanism by which G9a functions as an ERα coactivator. Along with the PHF20/MOF complex, G9a links the crosstalk between ERα methylation and histone acetylation governing the epigenetic regulation of hormonal gene expression.

2016-04-07 | GSE76507 | GEO

PHF20 and PHF20L1 in NSL complex

Project description:The methyl lysine readers PHF (plant homeodomain finger) 20 (PHF20) and its homolog PHF20 Like 1 (PHF20L1) are known components of the NSL (non-specific lethal) complex that regulates gene expression through its histone acetyltransferase activity. In the current model, both PHF homologs coexist in the same NSL complex although this was not formally tested; nor have the functions of PHF20 and PHF20L1 regarding NSL complex integrity and transcriptional regulation been investigated. By performing an in-depth biochemical and functional characterization, we define the association and contributions of the two methyl lysine reader homologs PHF20 and PHF20L1 to the NSL complex.

2022-04-04 | PXD029258 | Pride

COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function

Project description:Reversible acetylation of mitochondrial proteins is a regulatory mechanism central to adaptive metabolic responses. Yet, how such functionally relevant protein acetylation is achieved remains unexplored. Here, we reveal an unprecedented role of the MYST family lysine acetyltransferase MOF in energy metabolism via mitochondrial protein acetylation. Loss of MOF-KANSL complex members led to mitochondrial defects including fragmentation, reduced cristae density and impaired mitochondrial electron transport chain (mtETC) complex IV (CIV) integrity in primary mouse embryonic fibroblasts. We demonstrate COX17, a CIV assembly factor, as a bona fide acetylation target of MOF. Loss of COX17 or expression of its non-acetylatable mutant phenocopied the mitochondrial defects observed upon MOF depletion. The acetylation-mimetic COX17 rescues these defects and maintains CIV activity even in the absence of MOF, suggesting an activatory role of mtETC protein acetylation. Fibroblasts from MOF syndrome patients with intellectual disability also revealed respiratory defects that could be restored by alternative oxidase, acetylation-mimetic COX17 or mitochondrially targeted MOF. Overall, our findings highlight the critical role of MOF-KANSL complex in mitochondrial physiology and provide new insights into MOF syndrome.

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Altered levels of MOF and decreased levels of H4K16ac correlate with a defective DNA damage response (DDR).

Project description:Full title: Altered levels of MOF (member of MYST family histone acetyl transferase) and decreased levels of H4K16ac correlate with a defective DNA damage response (DDR). The human MOF gene encodes a protein that specifically acetylates histone H4 at lysine 16 (H4K16ac). Here we show that altered levels of H4K16ac correlate with a defective DNA damage response (DDR) to ionizing radiation (IR). The defect however is not due to altered expression of proteins involved in DDR. Specific inhibition of H4K16ac deacetylation in MOF-depleted cells rescued IR-induced abrogation of DDR. MOF was found associated with DNA-dependent protein kinase catalytic subunit (DNAPKcs), a protein involved in non-homologous end joining (NHEJ) repair, whose ATMdependent IR-induced phosphorylation was abrogated in MOF-depleted cells. Our data indicate that MOF depletion greatly decreased the repair of DNA double-strand breaks (DSBs) by NHEJ and homologous recombination (HR). In addition, the MOF protein activity associates with chromatin upon DNA damage and colocalizes with the synaptonemal complex in male meiocytes. We propose that MOF, through H4K16ac, plays a critical role in the cellular DNA damage response. Keywords: Cell type comparison HEK293 cells were transfected with plasmids encoding hMOF for over-expression of the histone acetyl transferase that leads to elevated levels of acetylation of Lysine 16 of histone H4. siRNA mediated knock-down of hMOF was performed to deplete the H4K16ac levels. Total RNA samples for expression profiling was obtained from wild type (293 cells without any treatment), hMOF over-expressed and hMOF knock-down 293 cell lines. Each sample was analyzed in triplicates using EGPF dsRNA treated samples as control.

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MOF-mediated histone H4 lysine 16 acetylation governs mitochondrial and ciliary functions by controlling promoter interactions (ChIP-Seq)

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