Gene Expression Profiling of WT and KDM3A Knocked out Cell
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE108921 | GEO | 2019/03/20
REPOSITORIES: GEO
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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.
2019-03-20 | GSE108920 | GEO
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-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
2014-10-15 | E-GEOD-62309 | biostudies-arrayexpress
Project description:The epigenetic modifier lysine-specific histone demethylase 3a (kdm3a) is specific for demethylation of mono- and di-methylated 9th lysine of histone H3 (H3K9me1/2) and belongs to the Jumonji domain-containing group of demethylases. Kdm3a is known to play significant roles during various biological and pathophysiological processes such as spermatogenesis and metabolism, determination of sex, androgen receptor-mediated transcription, and embryonic carcinoma cell differentiation. In the current study, we evaluated the physiological functions of kdm3a during Xenopus laevis embryogenesis. Spatiotemporal expression pattern indicated maternal nature of kdm3a, exhibiting its expression from early embryonic stages until tadpole stage, however considerable high level of expression were observed during the neurula stage of Xenopus development. Depleting kdm3a using kdm3a antisense morpholino oligonucleotides induced anomalies, such as head deformities and small-sized eyes. Our whole-mount in situ hybridization results demonstrated that kdm3a knockdown is associated with defects in neural crest formation and migration. Further, reverse transcription polymerase chain reaction revealed abnormal expression of neural markers in kdm3a morphants. RNA sequencing of kdm3a morphants indicated that kdm3a is implicated in mesoderm formation, cell adhesion, and metabolic processes of embryonic development. In conclusion, we suggest that kdm3a is critical for neural development during Xenopus embryogenesis and can be targeted for treatment of developmental disorders. The further detailed investigation is required to understand the molecular mechanism involved in neural development regulation by kdm3a.
2018-11-23 | GSE117754 | GEO
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
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.
2012-06-15 | GSE33841 | GEO
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
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
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.
2024-01-14 | GSE230341 | GEO
Project description:Heart disease and failure is a leading cause of mortality worldwide. Left ventricular hypertrophy (LVH) is a major risk factor for cardiovascular morbidity and mortality and the development of heart failure. Pathological LVH induced by sustained pressure-overload engages transcriptional programs including reactivation of canonical fetal genes and those inducing fibrosis. Histone lysine demethylases (KDMs) are emerging potent regulators of transcriptional reprogramming in cancer, though their potential role in abnormal growth and fibrosis in heart disease remains little understood. Here, we investigated gain and loss of function of an H3K9me2 specific demethylase, Kdm3a, in myocytes and in vivo, and show it promotes LVH and myocardial fibrosis in response to pressure-overload. Cardiomyocyte KDM3A activates the transcription of tissue-inhibitor of MMP type 1 (Timp1) with pro-fibrotic activity. By contrast, a pan-KDM inhibitor, JIB-04, suppresses TAC-induced LVH and fibrosis. JIB-04 inhibits KDM3A and suppresses the transcription of fibrotic genes that overlap with genes downregulated in Kdm3a-KO mice versus WT controls. Our study provides genetic and biochemical evidence for a pro-hypertrophic function of KDM3A and proof-of principle for pharmacological targeting of KDMs as an effective strategy to counter LVH and pathological fibrosis.
2018-10-09 | GSE120739 | GEO
Project description:Heart disease and failure is a leading cause of mortality worldwide. Left ventricular hypertrophy (LVH) and myocardial fibrosis are major risk factors for cardiovascular morbidity and mortality and the development of heart failure. Pathological LVH induced by sustained pressure-overload engages transcriptional programs including reactivation of canonical fetal genes and those inducing fibrosis. Histone lysine demethylases (KDMs) are emerging potent regulators of transcriptional reprogramming in cancer, though their potential role in abnormal growth and fibrosis in heart disease remains little understood. Here, we investigated gain and loss of function of an H3K9me2 specific demethylase, Kdm3a, in myocytes and in vivo, and show it promotes LVH and myocardial fibrosis in response to pressure-overload. Cardiomyocyte KDM3A activates the transcription of tissue-inhibitor of MMP type 1 (Timp1) with pro-fibrotic activity. By contrast, a pan-KDM inhibitor, JIB-04, suppresses TAC-induced LVH and fibrosis. JIB-04 inhibits KDM3A and suppresses the transcription of fibrotic genes that overlap with genes downregulated in Kdm3a-KO mice versus WT controls. Our study provides genetic and biochemical evidence for a pro-hypertrophic function of KDM3A and proof-of principle for pharmacological targeting of KDMs as an effective strategy to counter LVH and pathological fibrosis.
2018-10-09 | GSE120598 | GEO