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The S. cerevisiae histone demethylase Jhd1 fine-tunes the distribution of H3K36me2

ABSTRACT: Histone methylation plays important roles in the regulation of chromatin dynamics and transcription. Steady state levels of histone lysine methylation are regulated by a balance between enzymes that catalyze either the addition or removal of methyl groups. Using an activity-based biochemical approach, we recently uncovered the JmjC domain as an evolutionarily conserved signature motif for histone demethylases. Furthermore, we demonstrated that Jhd1, a JmjC domain-containing protein in S. cerevisiae, is an H3K36-specific demethylase. Here we report further characterization of Jhd1. Similar to its mammalian homolog, Jhd1-catalyzed histone demethylation requires iron and alpha-ketoglutarate as cofactors. Mutation and deletion studies indicate that the JmjC domain and adjacent sequences are critical for Jhd1 enzymatic activity, while the N-terminal PHD domain is dispensable. Overexpression of JHD1 results in a global reduction of H3K36 methylation in vivo. Finally, chromatin immunoprecipitation coupled microarray (ChIP-chip) studies reveal subtle changes in the distribution of H3K36me2 upon overexpression or deletion of JHD1. Our studies establish Jhd1 as a histone demethylase in budding yeast and suggest that Jhd1 functions to maintain the fidelity of histone methylation patterns along transcription units. Keywords: ChIP-chip

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE7627 | GEO | 2007/05/04

SECONDARY ACCESSION(S): PRJNA100253

REPOSITORIES: GEO

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The S. cerevisiae histone demethylase Jhd1 fine-tunes the distribution of H3K36me2

Project description:Histone methylation plays important roles in the regulation of chromatin dynamics and transcription. Steady state levels of histone lysine methylation are regulated by a balance between enzymes that catalyze either the addition or removal of methyl groups. Using an activity-based biochemical approach, we recently uncovered the JmjC domain as an evolutionarily conserved signature motif for histone demethylases. Furthermore, we demonstrated that Jhd1, a JmjC domain-containing protein in S. cerevisiae, is an H3K36-specific demethylase. Here we report further characterization of Jhd1. Similar to its mammalian homolog, Jhd1-catalyzed histone demethylation requires iron and alpha-ketoglutarate as cofactors. Mutation and deletion studies indicate that the JmjC domain and adjacent sequences are critical for Jhd1 enzymatic activity, while the N-terminal PHD domain is dispensable. Overexpression of JHD1 results in a global reduction of H3K36 methylation in vivo. Finally, chromatin immunoprecipitation coupled microarray (ChIP-chip) studies reveal subtle changes in the distribution of H3K36me2 upon overexpression or deletion of JHD1. Our studies establish Jhd1 as a histone demethylase in budding yeast and suggest that Jhd1 functions to maintain the fidelity of histone methylation patterns along transcription units. Keywords: ChIP-chip H3K36me2 ChIPs were performed on wild type, jhd1 knockout, and JHD1 overexpression yeast strains.

2010-06-11 | E-GEOD-7627 | biostudies-arrayexpress

Structural basis of paralog-specific KDM2A/B nucleosome recognition

Project description:The nucleosome acidic patch is a major interaction hub for chromatin, providing a platform for enzymes to dock and orient for nucleosome-targeted activities. In order to define the molecular basis of acidic patch recognition proteome-wide, we performed an amino acid resolution acidic patch interactome screen. We discovered that the histone H3 lysine 36 (H3K36) demethylase KDM2A, but not its closely related paralog, KDM2B, requires the acidic patch for nucleosome binding. These KDM2 family JumonjiC (JmjC) domain lysine demethylases are critical to heterochromatin formation and are commonly misregulated in cancer. Despite fundamental roles in transcriptional regulation in health and disease, the molecular mechanisms governing nucleosome substrate specificity of KDM2A/B, or any other JmjC lysine demethylases, remain unclear. We used a covalent JmjC inhibitor to solve cryo-EM structures of KDM2A and KDM2B trapped in action on the nucleosome. Our structures show that KDM2-nucleosome binding is paralog-specific and facilitated by dynamic nucleosomal DNA unwrapping and histone charge shielding that mobilize the H3K36 sequence for demethylation.

2023-02-14 | PXD032791 | Pride

Histone arginine demethylation by RDMe1

Project description:Histone methylation mainly occurs on lysine and arginine residues. While lysine methylation can be removed by LSD1 and JmjC domain-containing demethylases, the existence of histone arginine demethylases is highly controversial. Here, we performed a high-content cell-based screening of a cDNA library containing 2,500 nuclear proteins and identified RDMe1 as a histone arginine demethylase. Overexpression of RDMe1 in HEK293T cells reduces H3R2me1/2a and H4R3me1/2a levels. In vitro, RDMe1 specifically demethylates H3R2me1/2a and H4R3me1/2a, and generates formaldehyde and succinate. The enzymatic activity requires Fe(II) and α-ketoglutarate as cofactors. RDMe1 is mainly located in the nucleolar and regulates rRNA transcription by demethylating H3R2me2a. ChIP-seq reveals that RDMe1 demethylates H4R3me2a in the promoter in a genome-wide scale. NMR reveals that RDMe1 binds iron and substrate peptides with N and C termini, respectively. Mutation of the iron binding residues abolished the binding and the demethylase activity. Thus, we identify a histone arginine demethylase and reveal the reversibility of arginine methylation.

2022-01-09 | GSE124890 | GEO

KIAA1718 is a dual specific histone demethylase involved in early neural development

Project description:Histone methylation is a complex posttranslational modification regulating transcription and chromatin dynamics, and plays important roles in development and disease processes. Recent studies indicate that histone lysine methylation is a reversible modification and several JmjC-domain-containing proteins have been identified as histone lysine demethylases. Here we show that KIAA1718, a JmjC-domain-containing protein, is a histone demethylase. KIAA1718 demethylated dimethylation of H3 lysine 9 and 27 (H3K9me2 and H3K27me2), two important epigenetic marks associated with embryonic development6-10. In mouse embryonic stem cells (ESCs), KIAA1718 expression increased at the early phase of neural differentiation. RNA interference inhibition of KIAA1718 blocked neural differentiation and the effect was rescued by wild-type human gene, but not by a catalytically inactive mutant. In chick embryos, KIAA1718 is exclusively expressed in the epiblast cells of the primitive streak, an organizer contributing to neural induction. Knockdown of KIAA1718 resulted in defects in neural formation, while its overexpression led to neural expansion. The pro-neural effect is mediated through transcriptional activation of FGF4, a growth factor implicated in neural induction. Thus, our study identifies a dual specific histone demethylase as a novel epigenetic factor integrated with growth factor signaling, which has important roles in the early neural development. This SuperSeries is composed of the SubSeries listed below.

2009-11-04 | GSE18863 | GEO

KDM2B is a Histone H3K79 Demethylase and Induces Transcriptional Repression via SIRT1-mediated Chromatin Silencing

Project description:The methylation of histone H3 lysine 79 (H3K79) acts as an active chromatin marker and is enriched in actively transcribed regions of the genome. However, demethylase of this mark remains unknown despite intensive research. Here, we show that KDM2B (FBXL10), a member of the Jumonji C (JmjC) family of proteins and previously known for its histone H3K36 demethylase activity, is a di- and trimethyl H3K79 demethylase. We demonstrate that KDM2B induces transcriptional repression of HOXA7 and MEIS1 via occupancy of promoters and demethylation of H3K79. Furthermore, genome-wide analysis suggests that H3K79 methylation levels are increased when KDM2B is depleted, suggesting that KDM2B functions as an H3K79 demethylase in vivo. Finally, stable KDM2B-knockdown cell lines exhibited displacement of SIRT1, with concomitant increases in H3K79 methylation and H4K16 acetylation. Our findings identify KDM2B as an H3K79 demethylase and link its function to transcriptional repression via SIRT1-mediated chromatin silencing.

2017-10-21 | GSE89052 | GEO

A jumonji protein with E3 ligase and histone binding activities regulates transposon silencing in Arabidopsis

Project description:Transposable elements (TEs) make up a large proportion of eukaryotic genomes. As their mobilization creates genetic variation that threatens genome integrity, TEs are epigenetically silenced through several pathways and this may spread to neighboring sequences. JUMONJI (JMJ) proteins can function as anti-silencing factors and prevent silencing of genes next to TEs. Whether TE silencing is counterbalanced by the activity of anti-silencing factors is still unclear. Here, we characterize JMJ24 as a regulator of TE silencing. We show that loss of JMJ24 results in increased silencing of the DNA transposon AtMu1c, while overexpression of JMJ24 reduces silencing. JMJ24 has a JumonjiC (JmjC) domain and two RING domains. JMJ24 auto-ubiquitinates in vitro, demonstrating E3 ligase activity of the RING domain(s). JMJ24-JmjC binds the N-terminal tail of histone H3 and full-length JMJ24 binds histone H3 in vivo. JMJ24 activity is anti-correlated with histone H3 lysine 9 dimethylation (H3K9me2) levels at AtMu1c. Double mutant analyses with epigenetic silencing mutants suggest that JMJ24 antagonizes histone H3K9me2, and requires H3K9 methyltransferases for its activity on AtMu1c. Genome-wide transcriptome analysis indicates that JMJ24 affects silencing at additional TEs. Our results suggest that the JmjC domain of JMJ24 has lost demethylase activity but has been retained as a binding domain for histone H3. This is in line with phylogenetic analyses indicating that JMJ24 [with the mutated JmjC domain] is widely conserved in angiosperms. Taken together, this study assigns a role in TE silencing to a conserved JmjC-domain protein with E3 ligase activity, but no demethylase activity.

2016-03-18 | GSE72954 | GEO

Phosphorylation of methyltransferase Set2p and demethylase Jhd1p and its association with histone H3K36 methylation and stress response pathways in Saccharomyces cerevisiae

Project description:Histone lysine methylation is a key epigenetic modification that regulates eukaryotic transcription. In Saccharomyces cerevisiae, it is controlled by a reduced but evolutionarily conserved suite of methyltransferase (Set1p, Set2p, Dot1p, and Set5p) and demethylase (Jhd1p, Jhd2p, Rph1p, and Gis1p) enzymes. Many of these enzymes are extensively phosphorylated in vivo; however, the functions of specific phosphosites are poorly understood. Here, we comprehensively investigate the phosphoregulation of the yeast histone methylation network by analysing 40 phosphosites on six enzymes through mutagenesis. A total of 82 genomically-edited S. cerevisiae strains were generated and screened for changes in native H3K4, H3K36, and H3K79 methylation levels, and for sensitivity to environmental stress conditions. This demonstrated the functional relevance of phosphosites on methyltransferase Set2p (S6, S8, S10, and T127) and demethylase Jhd1p (S44) in the regulation of H3K36 methylation in vivo, and in the coordination of specific stress response pathways in budding yeast. Proteomic analysis of SET2 mutants revealed that phosphorylation site mutations lead to significant downregulation of membrane-associated proteins and processes, consistent with changes brought about by SET2 deletion. This study represents the first systematic investigation into the phosphoregulation of an entire epigenetic network in any eukaryote, and our findings establish phosphorylation as an important regulator of histone lysine methylation in S. cerevisiae.

2022-03-07 | PXD029088 | Pride

Next Generation Sequencing of sh-control and sh-KDM10A/KDM10B double knockdown HeLa Cells Transcriptomes

Project description:Histone methyl groups can be removed by histone demethylases. Although LSD1 and JmjC domain-containing proteins have been identified to be histone demethylases, enzymes responsible for many histone methylation states or sites are not identified. Here, we performed a high-content cell-based screening of a cDNA library containing 2,500 nuclear proteins and identified KDM10A as a histone demethylase specific for histone H4 lysine 20 (H4K20). Ectopic expression of KDM10A reduced the global levels of H4K20me1/2/3 in 293T cells. In vitro, KDM10A specifically demethylated H4K20me1/2/3 and generated formaldehyde. The enzymatic activity required Fe(II) and α-ketoglutarate as cofactors. Domain mapping indicated that the demethylase activity required its UBA domain. We also demonstrated that KDM10B, a protein homologous to KDM10A, had H4K20 demethylase activity in vitro and in vivo. ChIP-seq reveals that KDM10A/B demethylated H4K20 methylation at specific genomic loci in vivo. We further demonstrated that KDM10A/B activated the transcription of coding genes by demethylating H4K20me1 in the gene body, and the transcription of repetitive elements by demethylating H4K20me3 in intergenic regions. NMR analyses demonstrated that an HxxxE motif in the UBA domain is crucial for iron binding, mutation of these two residues abolished iron binding and the demethylase activity. Thus, we identified a family of UBA domain-containing proteins as histone demethylases.

2020-03-29 | GSE135988 | GEO

Histone Demethylation by a Family of UBA Domain-containing Proteins

2020-03-29 | GSE135986 | GEO

OsJMJ703, a Histone H3K4 Demethylase, Controls Transposon Activity in Rice

Project description:Retrotransposons are classified into long terminal repeat (LTR) or non-LTR retrotransoposons, and both types can mobilize in a “copy and paste” manner. Rice genome contains >40% of repetitive sequences or transposable elements (TEs) that scattered throughout the genome. TE activities are tightly regulated by distinct epigenetic mechanisms. Histone lysine methylation is catalyzed by SET domain group (SDG) protein and reversed by a family of Jumonji C (JmjC) domain-containing proteins. In rice, DNA methylation and histone methylation have been implicated in controlling copia-like LTR retrotransposon Tos17 activities. Whether any TEs are controlled by histone demethylase remains to be elusive. Here, we show that JMJ703 is a histone H3K4 specific demethylase in rice. Impaired JMJ703 disrupted genome-wide transcriptome and enhanced H3K4me3 resulting in pleiotropic defects. Two LINE elements, Karma and its N-terminal truncation were identified as direct targets of JMJ703 with increased frequency of transposition in jmj703, while Tos17 is unaffected. Our findings show that plants use H3K4me3 demethylase to constitutively remove active chromatin mark and maintain silencing status at a subset retrotransposons which localize in heterochromatin regions. Therefore, our work uncovers a novel mechanism to control retrotransposon activity by histone demethylation, which further strengthens the link between epigenetic silencing and genome stability. Examination of differences in H3K4 between jmj703 and wild type.

2013-01-01 | E-GEOD-41183 | biostudies-arrayexpress

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