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Epigenetic regulation of metabolic adaptation predicts response to Inositol hexakisphosphate (IP6) treatment in Group 4 medulloblastoma (RNA-seq, ChIP-seq)

ABSTRACT: Deregulation of chromatin modifiers plays an essential role in the pathogenesis of medulloblastoma (MB), the most common paediatric malignant brain tumour. Here, we identify a BMI1-dependent sensitivity to deregulation of inositol metabolism in a proportion of medulloblastoma. We demonstrate mTOR pathway activation and metabolic adaptation specifically in medulloblastoma of the molecular subgroup G4 characterised by a BMI1High;CHD7Low signature and show this can be counteracted by IP6 treatment. Finally, we demonstrate that IP6 synergises with cisplatin to enhance its cytotoxicity in vitro and extends survival in a pre-clinical BMI1High;CHD7Low xenograft model.

ORGANISM(S): Homo sapiens

PROVIDER: GSE154394 | GEO | 2021/03/04

REPOSITORIES: GEO

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Project description:Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by adenosine deaminases acting on RNA (ADARs), is a key post-transcriptional modification that regulates RNA splicing, stability, and translation. Dysregulation of ADAR activity caused by mutations in ADAR1 leads to Aicardi-Goutières syndrome (AGS), an autoimmune disorder characterized by aberrant activation of Melanoma differentiation-associated protein 5 (MDA5) by self RNA and excessive type I interferon production. Despite its biological and clinical relevance, the regulation of ADAR1 activity remains incompletely understood. Here, we show that ADAR1 protein levels and RNA editing activity in mammalian cells critically depend on the cofactor inositol hexakisphosphate (IP6). Using Inositol-pentakisphosphate 2-kinase (IPPK)-knockout cells, next-generation sequencing (NGS), and a cell-permeable IP6 prodrug (Pro-IP6), we demonstrate that IP6 depletion drastically reduces global RNA editing, while supplementation with Pro-IP6 restores and even enhances editing levels. In vitro ADAR1 translation and RNA editing assays revealed that IP6 contributes to the folding and full catalytic activity of ADAR1, and that inositol pentakisphosphate (1,3,4,5,6-IP5) can partially substitute IP6 as a cofactor. Molecular dynamics simulations and biochemical analyses identified the C6-phosphate of IP6 as a critical determinant of ADAR1 catalytic efficiency, functioning within a hydrogen-bonding network that indirectly governs Zn²⁺-ion positioning through interactions with key residues, including K1039 and N907. Notably, the AGS-associated N907S mutation impairs RNA editing, by altering IP6 coordination and introducing more dynamic situation in the hydrogen-bonding network of IP6 and Zn²⁺-ion. Together, these findings identify IP6 as an essential cofactor and regulator of ADAR1 activity. Through a network of interactions and the availability of IP6, this may represent a new strategy for therapeutically controlling RNA editing in the disease.

Project description:Trypanosoma cruzi is a protozoan parasite etiological agent of the vector-borne disease American trypanosomiasis, also known as Chagas disease. During its life cycle, T. cruzi undergoes some fundamental processes: metacyclogenesis (transition from epimastigote to metacyclic trypomastigote form) – occurring in the invertebrate host, amastigogenesis (transition from trypomastigote to amastigote form) and trypomastigogenesis (transition from amastigote to trypomastigote form) – both occurring within nucleated cells of the mammalian host, and finally epimastigogenesis (transition from trypomastigote to epimastigote forms) – which occurs as soon as the invertebrate host ingests trypomastigote forms during the bloodmeal. The precise mechanisms that regulate these processes remain elusive but certainly depend on kinases. The canonical function of the inositol hexakisphosphate kinases (IP6Ks) is to phosphorylate the phosphate groups from inositol hexaphosphate (IP6), leading to the formation of inositol pyrophosphates (PP-IPs). However, recent studies have been describing non-canonical functions for this kinase family. Here, after disrupting a single IP6K allele of T. cruzi and confirming its downregulation, we observed that the life cycle of this parasite was profoundly impaired. Epimastigote forms of T. cruzi IP6K-deficient showed morphological alterations, increased population presenting a dormant-like state (quiescence), and a reduced differentiation capacity during metacyclogenesis. The restricted metacyclic forms of T. cruzi IP6K-deficient that were able to differentiate had reduced infective potential (invasion rate) in human cardiomyocytes. Interestingly, 120 h after infection, the amastigote forms of T. cruzi IP6K-deficient showed an impaired ability to transform into trypomastigotes, with most of the population egressing from human cardiomyocytes without completing trypomastigogenesis. Transcriptomic data show that the levels of surface proteins (mucins and trans-sialidases) were altered in both epimastigote and trypomastigote forms in response to the low levels of IP6K, which helps explain our findings. Finally, we observed that the few trypomastigote forms of T. cruzi IP6K-deficient that egressed from human cardiomyocytes could not complete the epimastigogenesis. Together, our findings strongly suggest that IP6K is critical to sustain the T. cruzi life cycle. Thus, as the disruption of both IP6K alleles did not generate viable parasites and the similarity relative to its human homolog is ~15%, this kinase could be a potential target for drug development against Chagas disease.

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Epigenetic regulation of metabolic adaptation predicts response to Inositol hexakisphosphate (IP6) treatment in Group 4 medulloblastoma (RNA-seq, ChIP-seq)

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