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Specific phosphorylation of histone demethylase KDM3A determines target gene expression in response to heat shock

ABSTRACT: Histone lysine (K) residues, which are modified by methyl- and acetyl-transferases, diversely regulate RNA synthesis. Unlike the ubiquitously activating effect of histone K acetylation, the effects of histone K methylation vary with the number of methyl groups added and with the position of these groups in the histone tails. Histone K demethylases (KDMs) counteract the activity of methyl-transferases and remove methyl group(s) from specific K residues in histones.KDM3A (also known as JHDM2A or JMJD1A) is an H3K9me2/1 demethylase. KDM3Aperforms diverse functions via the regulation of its associated genes, which are involved in spermatogenesis, metabolism, and cell differentiation. However, the mechanism by which the activity of KDM3A is regulated is largely unknown. First, we demonstrated that mitogen- and stress-activated protein kinase 1 (MSK1) specifically phosphorylates KDM3A at Ser264 (pKDM3A), which is enriched in the regulatory regions of gene loci in the human genome under heat shock conditions. p-KDM3A directly interacts with and is recruited by the transcription factor Stat1 to activate KDM3A target genes. The demethylation of H3K9me2 at the Stat1 binding site specifically depends on the co-expression of p-KDM3A under heat shock conditions. In contrast to heat shock treatment, IFN-M-NM-3 treatment does not phosphorylate KDM3A via MSK1, thereby abrogating its downstream effects. To our knowledge, this is the first evidence that a KDM can be modified via phosphorylation to determine its specific binding to target genes in response to cellular stress. 3 ChIP samples and two input as controls

ORGANISM(S): Homo sapiens

SUBMITTER: Ye Zhang

PROVIDER: E-GEOD-62309 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Specific phosphorylation of histone demethylase KDM3A determines target gene expression in response to heat shock

Project description:Histone lysine (K) residues, which are modified by methyl- and acetyl-transferases, diversely regulate RNA synthesis. Unlike the ubiquitously activating effect of histone K acetylation, the effects of histone K methylation vary with the number of methyl groups added and with the position of these groups in the histone tails. Histone K demethylases (KDMs) counteract the activity of methyl-transferases and remove methyl group(s) from specific K residues in histones.KDM3A (also known as JHDM2A or JMJD1A) is an H3K9me2/1 demethylase. KDM3Aperforms diverse functions via the regulation of its associated genes, which are involved in spermatogenesis, metabolism, and cell differentiation. However, the mechanism by which the activity of KDM3A is regulated is largely unknown. First, we demonstrated that mitogen- and stress-activated protein kinase 1 (MSK1) specifically phosphorylates KDM3A at Ser264 (pKDM3A), which is enriched in the regulatory regions of gene loci in the human genome under heat shock conditions. p-KDM3A directly interacts with and is recruited by the transcription factor Stat1 to activate KDM3A target genes. The demethylation of H3K9me2 at the Stat1 binding site specifically depends on the co-expression of p-KDM3A under heat shock conditions. In contrast to heat shock treatment, IFN-γ treatment does not phosphorylate KDM3A via MSK1, thereby abrogating its downstream effects. To our knowledge, this is the first evidence that a KDM can be modified via phosphorylation to determine its specific binding to target genes in response to cellular stress.

2014-10-15 | GSE62309 | GEO

Vitamin C Induces Specific Demethylation of H3K9me2 in Mouse Embryonic Stem Cells via Kdm3a/b

Project description:Histone methylation patterns regulate gene expression and are highly dynamic during development. The erasure of histone methylation is carried out by histone demethylase enzymes. We had previously shown that vitamin C enhances the activity of Tet enzymes in embryonic stem (ES) cells, leading to DNA demethylation and activation of germline genes. We report here that vitamin C induces a remarkably specific demethylation of histone H3 lysine 9 dimethylation (H3K9me2) in ES cells. Vitamin C treatment reduces global levels of H3K9me2, but not other histone methylation marks analyzed, as measured by Western blot, immunofluorescence and mass spectrometry. Vitamin C leads to widespread loss of H3K9me2 at large chromosomal domains as well as gene promoters and repeat elements. Vitamin C-induced loss of H3K9me2 occurs rapidly within 24 hours and is reversible. Importantly, we found that the histone demethylases Kdm3a and Kdm3b are required for vitamin C-induced demethylation of H3K9me2. Moreover, we show that vitamin C-induced Kdm3a/b-mediated H3K9me2 demethylation and Tet-mediated DNA demethylation are independent processes. Lastly, we document Kdm3a/b are partially required for the up-regulation of germline genes by vitamin C. These results reveal a specific role for vitamin C in histone demethylation in ES cells, and document that DNA methylation and H3K9me2 cooperate to silence germline genes in pluripotent cells.

2017-06-30 | GSE84009 | GEO

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m6A in 5’ untranslated regions promotes cap-independent translation of mRNA

Project description:N6-methyladenosine (m6A) is a widespread internal RNA modification whose function is poorly understood. Here we report that m6A residues within the 5'UTR promote a novel form of cap-independent translation which is mediated through an interaction between m6A residues and the translation initiation factor, eIF3. We performed m6A profiling in cells subjected to heat shock stress and observed increased 5'UTR methylation after heat shock. For these studies, we used single-nucleotide resolution m6A mapping (miCLIP), which enables the detection of m6A residues separately from m6Am residues. Thus, the goal of these experiments was to identify m6A residues which are increased in the 5'UTR after heat shock stress.

2015-10-26 | GSE73405 | GEO

Role for KDM3A in ciliogenesis

Project description:Cilia are dynamic antennae that sense the extracellular environment adjusting their length to maintain homeostasis. Mutant mouse models for the lysine demethylase KDM3A (JMJD1A, JMHD2A) share phenotypic features with human ciliopathies, including obesity and metabolic syndrome. Here we show that cilia of Kdm3a mutants are unstable with dysregulated length ranges accumulating intraflagellar transport proteins (IFTs) at the ciliary tip. RNA sequencing and mass-spectrometry identified actin cytoskeleton as the most miss-regulated feature during the ciliary cycle of KDM3A null cells and revealed that IFT81 contains Nε-methylated lysines in vivo to which recombinant KDM3A binds without subsequent demethylation. Mutations in these IFT81 methyl-lysine residues however stabilize KDM3A null cilia and potentiate ciliogenesis surpassing wild type cells; a synergism phenocopied by wild type cultures through the simultaneous destabilization of the actin cytoskeleton when over-expressing IFT81 lysine-mutants. Our work reveals that ciliogenesis requires the coordinated release of cytoskeletal constrains and the presence of intraflagellar transport proteins which KDM3A integrates aided by post-translationally modifiable lysine residues in IFT81.

2018-07-11 | PXD004334 | Pride

Genome-wide maps of chromatin state in HCT116 cells.

Project description:We identified KDM3A, a demethylase of histone H3K9me1/2, as a positive regulator for hippo target genes. We found that H3K27ac upregulation is highly correlated with gene activation, but not H3K4me3; and transcription repression of certain TEAD1 target genes, such as BBC3, is important for the pathway function. KDM3A knockout caused upregulation of H3K9me2 mainly on TEAD1-binding enhancers rather than gene bodies, leading to decrease of H3K27ac and TEAD1 binding on enhancers and impaired transcription. We identified KDM3A, a demethylase of histone H3K9me1/2, as a positive regulator for hippo target genes. We found that H3K27ac upregulation is highly correlated with gene activation, but not H3K4me3; and transcription repression of certain TEAD1 target genes, such as BBC3, is important for the pathway function. KDM3A knockout caused upregulation of H3K9me2 mainly on TEAD1-binding enhancers rather than gene bodies, leading to decrease of H3K27ac and TEAD1 binding on enhancers and impaired transcription.

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The histone demethylase Kdm3a is essential to progression through differentiation

Project description:Histone demethylation has important roles in regulating gene expression and forms part of the epigenetic memory system that regulates cell fate and identity, by still poorly understood mechanisms. Here we examined the role played by the histone demethylase Kdm3a, which demethylates lysine 9 of histone H3, during cellular differentiation. Using F9 mouse embryonal carcinoma cells as a model for progression through terminal differentiation, we showed that Kdm3a is essential to differentiation into parietal endoderm-like (PE) cells. On gene expression microarrays, we found several genes whose expression is upregulated by Kdm3a during endoderm differentiation, including the three developmental master players Dab2, Pdlim4, and FoxQ1. The role of Kdm3a as a transcriptional activator of these genes was correlated with its effect by demethylating dimethyl-lysine 9 of histone H3 (H3K9me2) at their promoters. We further demonstrated that Dab2 depletion, like Kdm3a depletion, prevents F9 cells from fully differentiating into PE cells. Nevertheless, the only overexpression of Dab2 in Kdm3a-depleted cells is not sufficient to completely restore the PE differentiation in Kdm3a-knockdown cells. Overall, our findings reveal that Kdm3a is crucial for progression through terminal differentiation, likely by regulating the expression of a set of master players in endoderm differentiation. The emergence of Kdm3a as a key modulator of cell fate decision strengthens the notion that histone demethylases are at the nexus of cell differentiation and development.

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KDM3A and KDM3B maintain naïve pluripotency through regulation of alternative splicing

Project description:Histone modifying enzymes play a central role in maintaining cell identity by establishing a conducive chromatin environment for lineage specific transcription factor activity. Pluripotent embryonic stem cells (ESCs) identity is characterized by lower abundance of gene repression associated histone modifications that enables rapid response to differentiation cues. The KDM3 histone demethylase family remove the repressive histone H3 lysine 9 dimethylation (H3K9me2). Here we uncover a surprising role for the KDM3 proteins in the maintenance of the pluripotent state through post-transcriptional regulation. We find through immunoaffinity purification of the KDM3A or KDM3B interactome and proximity ligation assays that KDM3A and KDM3B interact with the RNA processing factors such as EFTUD2 and PRMT5. By generating double “degron” ESCs to degrade KDM3A and KDM3B in the rapid timescale of splicing, we find altered splicing independent of H3K9me2 status. These splicing changes partially resemble the splicing pattern of the more blastocyst like ground state of pluripotency and occurred in important chromatin and transcription factors such as Dnmt3b, Tbx3 and Tcf12. Our findings reveal non-canonical roles of histone modifying enzymes in splicing to regulate cell identity. Cells were plated, allowed to adhere overnight, then treated for four hours with dTAG-13.

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HP1a recruitment to promoters is independent of H3K9 methylation in Drosophila melanogaster

Project description:Heterochromatin protein 1 (HP1) proteins are important regulators of heterochromatin mediated gene silencing and chromosome structure and it is well known as the reader of the heterochromatin mark methylation of histone H3 lysine 9 (H3K9me). In Drosophila three different histone lysine methyl transferases (HKMTs) are associated with the methylation of H3K9; Su(var)3-9, Setdb1 and G9a. To gain insights on the dependence of HP1a on the three different HKMTs, the division of labor between these methyl transferases and the dependence of HP1a on H3K9me we have studied HP1a binding in relation to H3K9me in mutants of these HKMTs. We show that Su(var)3-9 is responsible for the HP1a H3K9me-dependent binding in pericentromeric regions while Setdb1 controls the HP1a H3K9me-dependent binding to cytological region 2L:31 and together with POF chromosome 4. HP1a binds to the promoters and within gene bodies of active genes in these three regions. More importantly, HP1a bound at promoters of active genes are independent of H3K9me and POF and is associated to heterochromatin protein 2 (HP2) and open chromatin. Our results supports a model where HP1a nucleates with high affinity independent of H3K9me in promoters of active genes and then spreads via H3K9 methylation and transient looping contacts with those H3K9me target sites. In total 44 samples; 2 replicates for each genotype and for each ChIP (HP1a, H3K9me2 and H3K9me3)

2012-12-21 | E-GEOD-38366 | biostudies-arrayexpress

Homo sapiens

Project description:Specific phosphorylation of histone demethylase KDM3A determines target gene expression in response to heat shock

| PRJNA263810 | ENA