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The ribosomal prolyl-hydroxylase OGFOD1 decreases during cardiac differentiation, modulates translation and spliceosomal processes

ABSTRACT: In this study we provide the gene expression profiles and MISO analyses for alternative splicing events such as exon skipping in wildtype versus OGFOD1 (oxoglutarate, glucose and iron dependent protein 1)-knock-out iPSC-derived cardiomyocytes, we further compare the profiles to wildtype which were treated with a drug inhibiting α-ketoglutarate-dependent hydroxylases (dimethyloxalylglycine) versus vehicle control. Altered translation and splicing processes play a role in differentiation processes and have been shown to be involved in disease progression in e.g. heart failure. OGFOD1 is a ribosomal prolyl-hydroxylase and which influences translation, here we show its further importance in cardiac differentiation and alternative splicing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE130521 | GEO | 2019/07/26

REPOSITORIES: GEO

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Project description:Acute Myeloid Leukemia (AML) commonly relapses after initial chemotherapy response. We assessed metabolic adaptations in a minimal-residual disease setting of chemoresistant cells in vivo before overt relapse, identifying elevated branched-chain amino acid (BCAA) levels in patient-derived xenografts (PDX) and immunophenotypically identified leukemia stem cells from AML patients. Notably, this was associated with increased BCAA transporter expression without indications for higher BCAA catabolism. Restricting of BCAAs further reduced chemoresistant AML cells but relapse still occurred. Among the persisting cells we found an unexpected Acute Myeloid Leukemia (AML) commonly relapses after initial chemotherapy response. We assessed metabolic adaptations in chemoresistant cells in vivo before overt relapse, identifying altered branched-chain amino acid (BCAA) levels in patient-derived xenografts (PDX) and immunophenotypically identified leukemia stem cells from AML patients. Notably, this was associated with increased BCAA transporter expression with low BCAA catabolism. Restricting of BCAAs further reduced chemoresistant AML cells but relapse still occurred. Among the persisting cells we found an unexpected increase in protein production. This was accompanied by elevated translation of 2-oxoglutarate-and-iron-dependent oxygenase 1 (OGFOD1), a known ribosomal dioxygenase that adjusts the fidelity of tRNA anticodon pairing with coding mRNA1–3 and upregulates protein synthesis in AML driving disease aggressiveness. Inhibiting OGFOD1 impaired translation processing, decreased protein synthesis and improved animal survival even with chemoresistant AML through regulation of protein synthesis. Leukemic cells can therefore persist despite the stress of chemotherapy and nutrient deprivation through adaptive control of translation while sparing normal hematopoiesis. Targeting OGFOD1 may offer a distinctive, translation modifying means of reducing the chemopersisting cells that drive relapse.

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The ribosomal prolyl-hydroxylase OGFOD1 decreases during cardiac differentiation, modulates translation and spliceosomal processes

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