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Human Nalm6 Cells: WT vs. OGFOD1 KO

ABSTRACT: The 2-OG-Fe(II) dioxygenase family are critical for cellular adaptation to changes in oxygen concentration. We found that cells with OGFOD1 gene silencing in this family showed resistance to cell death under ischemia, and cDNA microarray analysis of OGFOD1 knockout human cells revealed downregulation of ATPAF1. Although reintroduction of the OGFOD1 wild-type gene to OGFOD1 KO cells restored ATPAF1 mRNA levels, the catalytically inactive OGFOD1 mutant did not.

ORGANISM(S): Homo sapiens

PROVIDER: GSE21557 | GEO | 2010/04/29

SECONDARY ACCESSION(S): PRJNA126229

REPOSITORIES: GEO

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human Nalm6 Cells: WT vs. OGFOD1 KO

Project description:The 2-OG-Fe(II) dioxygenase family are critical for cellular adaptation to changes in oxygen concentration. We found that cells with OGFOD1 gene silencing in this family showed resistance to cell death under ischemia, and cDNA microarray analysis of OGFOD1 knockout human cells revealed downregulation of ATPAF1. Although reintroduction of the OGFOD1 wild-type gene to OGFOD1 KO cells restored ATPAF1 mRNA levels, the catalytically inactive OGFOD1 mutant did not. wild-type vs. OGFOD1 knock-out cells

2010-04-29 | E-GEOD-21557 | biostudies-arrayexpress

OGFOD1 Regulates Translation to Alter Hypertrophy Susceptibility

Project description:Cardiac hypertrophy, a precursor for heart failure, requires increased translation. However, little is known of the mechanisms that regulate translation in hypertrophy. Members of the 2-oxoglutarate-dependent dioxygenase family regulate several aspects of gene expression, including translation. An important member of this family is OGFOD1. Here, we show OGFOD1 accumulates in failing human hearts. Upon OGFOD1 deletion, murine hearts showed transcriptomic and proteomic changes, with only 21 factors (0.6%) changing in the same direction at both the mRNA and protein levels. Additionally, OGFOD1-KO mice were protected from induced hypertrophy, supporting a role for OGFOD1 in the cardiac response to chronic stress.

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ABHD11 maintains 2-oxoglutarate metabolism by preserving functional lipoylation of the 2-oxoglutarate dehydrogenase complex

Project description:2-oxoglutarate (2-OG or α-ketoglutarate) relates mitochondrial metabolism to cell function by modulating the activity of 2-OG dependent dioxygenases involved in the hypoxia response and DNA/histone modifications. However, metabolic pathways that regulate these oxygen and 2-OG sensitive enzymes remain poorly understood. Here, using CRISPR Cas9 genome-wide utagenesis to screen for genetic determinants of 2-OG levels, we uncover a redox sensitive mitochondrial lipoylation pathway, dependent on the mitochondrial hydrolase ABHD11, that signals changes in mitochondrial 2-OG metabolism to 2-OG dependent dioxygenase function. ABHD11 loss or inhibition drives a rapid increase in 2-OG levels by impairing lipoylation of the 2-OG dehydrogenase complex (OGDHc) – the rate limiting step for mitochondrial 2-OG metabolism. Rather than facilitating lipoate conjugation, ABHD11 associates with the OGDHc and maintains catalytic activity of lipoyl domain by preventing the formation of lipoyl adducts, highlighting ABHD11 as a regulator of functional lipoylation and 2-OG metabolism.

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The FAM46C gene encodes a non-canonical poly(A) polymerase and acts as an onco-suppressor in multiple myeloma

Project description:FAM46C is one of the most frequently mutated genes in multiple myeloma (MM) and encodes a protein of unknown function. Using a combination of in vitro and in vivo approaches, we demonstrate that FAM46C encodes an active cytoplasmic non-canonical poly(A) polymerase, which enhances mRNA stability and gene expression. Moreover, we also found that the reintroduction of active FAM46C into MM cell lines, but not its catalytically-inactive mutant, leads to broad polyadenylation and stabilization of mRNAs strongly enriched with those encoding endoplasmic reticulum-targeted proteins and induced cell death. This is, to our knowledge, the first report that directly associates cytoplasmic poly(A) polymerase with carcinogenesis. Furthermore, our data suggest that the human genome encodes at least eleven non-canonical poly(A) polymerases with four FAM46 family members. Since FAM46 proteins are differentially expressed during development, these proteins may positively regulate transcript stability and translational rate in a tissue-specific manner.

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Context Dependent Effects of Ascorbic Acid Treatment in TET2 Mutant Myeloid Neoplasia

Project description:Loss-of-function TET2 mutations (TET2MT) are common in myeloid neoplasia. TET2, a DNA dioxygenase, requires 2-oxoglutarate and Fe(II) to oxidize 5-methylcytosine. TET2MT thus result in hypermethylation and transcriptional repression. Ascorbic acid (AA) increases dioxygenase activity by facilitating Fe(III)/Fe(II) redox reaction and may alleviate some biological consequences of TET2MT by restoring dioxygenase activity. Here, we report the utility of AA in the prevention of TET2MT MN, clarify the mechanistic underpinning of the TET2-AA interactions, and demonstrate that the ability of AA to restore TET2 activity in cells depends on N- and C-terminal lysine acetylation and nature of TET2MT. Consequently, pharmacologic modulation of acetyltransferases and histone deacetylases may regulate TET dioxygenase-dependent AA effects. Thus, our study highlights the contribution of factors that may enhance or attenuate AA effects on TET2 and provides a rationale for novel therapeutic approaches including combinations of AA with class I/II HDAC inhibitor or sirtuin activators in TET2MT leukemia.

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Ascorbic acid reprogrames epigenome and epitranscriptome by recycling Fe (III) into Fe (II) in the catalytic cycle of dioxygenases (m6A)

Project description:Ascorbic acid has been reported to stimulate DNA iterative oxidase TET enzymes, Jumonji C-domain-containinghistone demethylase and potentially RNA m6A demethylase FTO and ALKBH5 as a cofactor. Although ascorbic acid has been widely investigated in reprogramming DNA and histone methylation status in vitro, in cell lines and mouse models, its specific role in the catalytic cycle of dioxygenases remains enigmatic. Here we systematically investigated the stimulation of ascorbic towards TET2, ALKBH3, histone demethylases and FTO. We find that ascorbic acid reprograms epitranscrip-tome by erasing the hypermethylated m6A sites. Biochemistry and Electron spin resonance (ESR) assays demonstrate that ascorbic acid enters the active pocket of dioxygenases, reduces Fe (III), either incorporated upon protein synthesis or generated upon rebounding the hydroxyl radical during oxidation, into Fe (II). Finally, we propose a new model for the catalytic cycle of dioxygenases by adding in the essential dynamic cofactor, ascorbic acid. Ascorbic acid refreshes and regenerates inactive dioxygenase through recycling Fe (III) into Fe (II) in a dynamic “hit-and-run” manner.

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Ascorbic acid reprogrames epigenome and epitranscriptome by recycling Fe (III) into Fe (II) in the catalytic cycle of dioxygenases (RNA-Seq)

2024-02-01 | GSE242759 | GEO

Development of potent and selective KDM5 covalent inhibitors

Project description:Histone lysine demethylase (KDMs) are involved in the dynamic regulation of gene expression by reversible regulation of the methylation levels on lysine residues in histone tails. Among the KDMs, the jumonji (JmjC)-domain-containing KDMs (KDM2-7) are Fe(II), 2- OG (α-ketoglutarate) and molecular oxygen-dependent enzymes that employ an oxygenase mechanism to demethylate specific methylation states at various histone sites. KDMs play a critical role in several biological processes such as cell differentiation, inflammation, cancer progression and resistance. Achieving selectivity over the different families of KDMs has been a major challenge. Here we report potent and selective KDM5 covalent inhibitors designed to target a cysteine residue only present in the KDM5 sub-family. In vitro assays show that compounds are selective for the KDM5 sub-family, showing potencies in the low nanomolar range, with higher affinity for KDM5A/B. The covalent binding to the targeted proteins was proved by MS. A kinetic approach was studied in order to describe the components of overall inhibitor potency (reversible binding and chemical reactivity), showing a time-dependent decrease of IC50 values for irreversible inhibition. Additional 2-OG competition assays show that compounds were non 2-OG competitive and target engagement and ChIPs-seq assays showed that the compounds inhibited the KDM5 members in cells in the low micromolar and they induce a global increase of the H3K4Me3 mark.

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Mouse ES cells expressing catalytically inactive Ring1B display impaired Ring1B and H3K27me3 deposition.

Project description:ChIP-seq for H3K27me3 and Ring1B was performed in WT mESCs and mESCs containing catalytically inactive Ring1B (I53A mutant). Cells expressing catalytically inactive Ring1B maintain the spatial distribution of Ring1B and H3K27me3 but at reduced levels. These findings support the notion that PRC2 recruitment is, in part, dependent on H2A ubiquitination (H2AK119ub). Two biological replicates were performed for Ring1B and H3K27me3 ChIPs in WT and Ring1B I53A/I53A mouse ESCs. Input chromatin was sequenced for each replicate as a control for ChIP enrichment.

2015-09-20 | E-GEOD-69955 | biostudies-arrayexpress

Mouse ES cells expressing catalytically inactive Ring1B display impaired Ring1B and H3K27me3 deposition.

2015-09-20 | GSE69955 | GEO