Histone Demethylases KDM3A and KDM4C regulate mesenchymal stromal cell senescence and bone aging through condensin-mediated heterochromatin organization
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ABSTRACT:
PROVIDER: PRJNA549942 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9332760.fastq.gz | Fastqsanger.gz | |||
| SRR9332761.fastq.gz | Fastqsanger.gz | |||
| SRR9332762.fastq.gz | Fastqsanger.gz | |||
| SRR9332763.fastq.gz | Fastqsanger.gz | |||
| SRR9332764.fastq.gz | Fastqsanger.gz |
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Project description:Epigenomic changes and stem cell exhaustion are two hallmarks of aging. Accumulating evidence suggest that MSC senescence could perpetuate aging or age-related diseases. Here we report that two H3K9 demethylases KDM3A and KDM4C regulate heterochromatin reorganization via transcriptionally activating condensin components NCAPD2 and NCAPG2 in aging MSCs. Suppression of KDM3A or KDM4C leads to robust DNA damage response and aggravates cellular senescence, whereas overexpression of KDM3A/KDM4C or NCAPD2 directly promotes heterochromatin reorganization and blunts DNA damage response. MSCs derived from kdm3a-/- mice exhibit compromised heterochromatin organization machinery and are more susceptible to genotoxic damage, which are associated with accelerated bone aging. Consistently, analysis of human bone marrow MSCs and transcriptome database for other human adult stem cells reveals inverse correlation of KDM3A and KDM4C with aging. Taken together, the present finding unveils a novel function of histone demethylases as a surveillance mechanism to restrain DNA damage accumulation via transcriptionally activating condensins during stem cell aging, which provides potential targets for the diagnosis and intervention of human aging and geriatric diseases.
2019-12-01 | GSE133098 | GEO
Project description:Epigenomic changes and stem cell deterioration are two hallmarks of aging. Accumulating evidence suggest that senescence of mesenchymal stromal cells (MSCs) perpetuates aging or age-related diseases. Here we report that two H3K9 demethylases, KDM3A and KDM4C, regulate heterochromatin reorganization via transcriptionally activating condensin components NCAPD2 and NCAPG2 during MSC senescence. Suppression of KDM3A or KDM4C by either genetic or biochemical approach leads to robust DNA damage response and aggravates cellular senescence, whereas overexpression of KDM3A/KDM4C or NCAPD2 promotes heterochromatin reorganization and blunts DNA damage response. Moreover, MSCs derived from Kdm3a-/- mice exhibit defective chromosome organization and exacerbated DNA damage response, which are associated with accelerated bone aging. Consistently, analysis of human bone marrow MSCs and transcriptome database reveals inverse correlation of KDM3A/KDM4C and/or NCAPD2/NCAPG2 with aging. Taken together, the present finding unveils that H3K9 demethylases function as a surveillance mechanism to restrain DNA damage accumulation in stem cells during aging.
| S-EPMC6888768 | biostudies-literature
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:We have mapped transcriptional changes after depletion of the histone demethylases JMJD2C/GASC1/KDM4C and JMJD2A/KDM4A alone or in combination in the esophageal squamous carcinoma cell line, KYSE150. The KYSE150 cell line contains an amplification of the JMJD2C locus.
2014-01-09 | GSE53892 | 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: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:We have mapped transcriptional changes after depletion of the histone demethylases JMJD2C/GASC1/KDM4C and JMJD2A/KDM4A alone or in combination in the esophageal squamous carcinoma cell line, KYSE150. The KYSE150 cell line contains an amplification of the JMJD2C locus. RNA was extracted from KYSE150 cells transfected with shRNAs targeting JMJD2C and/or JMJD2A. The experiment was performed in triplicates and expression levels analyzed using Affymetrix microarrays.
2014-01-09 | E-GEOD-53892 | biostudies-arrayexpress
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: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