Summary
Metabolism and gene regulations act in concert to shape cellular identity and plasticity. One major line of crosstalk occurs through metabolites such as acyl-CoAs, which are inscribed on histones as posttranslational modifications (PTMs) to be subsequently recognised by reader proteins, resulting in initiation of specific transcriptional programs. The increasing identification of novel PTMs necessitates thorough characterisation, however still remain largely underexplored. For instance, the presence of non-acetyl acyl-Lys PTMs such as crotonylation with YEATS-reader proteins identified to bind these PTMs suggests complex gene regulation programs. However, despite the clinical relevance of YEATS-proteins in various cancers, little is known about their acyl-reading activity and transcriptional consequences. Therefore, this proposal aims to close multiple knowledge gaps regarding overall function and mechanism of the metabolism/acyl-PTM/YEATS communication axis. Considering the metabolic context, I furthermore propose epigenetic YEATS action to be determined by direct interactions with metabolic proteins.
Thus, I will first establish an inducible YEATS-degradation platform to characterise the genomic context under various acylate conditions. Next, I will implement a fluorescence-based cell reporter system, which shall reveal putative interactors upon transfection with a CRISPR-KO library targeting metabolic enzymes. Lastly, hits will be biophysically characterized, their metabolic impact within the epigenetic context determined and co-dependencies on relevant cancer cell lines tested. The interdisciplinary approach entailing state-of-the-art chemical and molecular biology tools will be combined with high-throughput screening methods and bioinformatic analyses. Besides elucidating general principles of the metabolism-YEATS epigenetics crosstalk, the results will provide valuable information for novel therapeutic avenues by exploiting identified co-dependencies.
Thus, I will first establish an inducible YEATS-degradation platform to characterise the genomic context under various acylate conditions. Next, I will implement a fluorescence-based cell reporter system, which shall reveal putative interactors upon transfection with a CRISPR-KO library targeting metabolic enzymes. Lastly, hits will be biophysically characterized, their metabolic impact within the epigenetic context determined and co-dependencies on relevant cancer cell lines tested. The interdisciplinary approach entailing state-of-the-art chemical and molecular biology tools will be combined with high-throughput screening methods and bioinformatic analyses. Besides elucidating general principles of the metabolism-YEATS epigenetics crosstalk, the results will provide valuable information for novel therapeutic avenues by exploiting identified co-dependencies.
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| Web resources: | https://cordis.europa.eu/project/id/101106260 |
| Start date: | 01-08-2023 |
| End date: | 31-07-2025 |
| Total budget - Public funding: | - 183 600,00 Euro |
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Original description
Metabolism and gene regulations act in concert to shape cellular identity and plasticity. One major line of crosstalk occurs through metabolites such as acyl-CoAs, which are inscribed on histones as posttranslational modifications (PTMs) to be subsequently recognised by reader proteins, resulting in initiation of specific transcriptional programs. The increasing identification of novel PTMs necessitates thorough characterisation, however still remain largely underexplored. For instance, the presence of non-acetyl acyl-Lys PTMs such as crotonylation with YEATS-reader proteins identified to bind these PTMs suggests complex gene regulation programs. However, despite the clinical relevance of YEATS-proteins in various cancers, little is known about their acyl-reading activity and transcriptional consequences. Therefore, this proposal aims to close multiple knowledge gaps regarding overall function and mechanism of the metabolism/acyl-PTM/YEATS communication axis. Considering the metabolic context, I furthermore propose epigenetic YEATS action to be determined by direct interactions with metabolic proteins.Thus, I will first establish an inducible YEATS-degradation platform to characterise the genomic context under various acylate conditions. Next, I will implement a fluorescence-based cell reporter system, which shall reveal putative interactors upon transfection with a CRISPR-KO library targeting metabolic enzymes. Lastly, hits will be biophysically characterized, their metabolic impact within the epigenetic context determined and co-dependencies on relevant cancer cell lines tested. The interdisciplinary approach entailing state-of-the-art chemical and molecular biology tools will be combined with high-throughput screening methods and bioinformatic analyses. Besides elucidating general principles of the metabolism-YEATS epigenetics crosstalk, the results will provide valuable information for novel therapeutic avenues by exploiting identified co-dependencies.
Status
SIGNEDCall topic
HORIZON-MSCA-2022-PF-01-01Update Date
31-07-2023
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