Summary
Regulation of transcription is orchestrated by a complex combination of histone posttranslational modifications (PTMs), but how their co-occurrence in the same cell regulate gene expression is still poorly understood. Recently, novel histone acylations have been identified, namely propionylation (pr) and butyrylation (bu). They co-exist with acetylation (ac), arise from cellular metabolism, and are key candidates to fine-tune chromatin activity and transcription. This project will answer fundamental questions on the role of acylations in gene regulation and their co-occurrence in single cells, and provide novel insights into metabolic disorders (propionic acidemia; PA), where histone acylations are altered.
Through this project, I will generate the first genome-wide histone acylation map in single cells, functionally link their co-occurrence with gene expression, and establish the impact of a metabolic disease on histone acylations and transcription. Our preliminary data showed that histone H4K16ac/pr/bu play key roles in chromatin activity and could thus regulate transcription, and are impaired in livers of a PA mouse model. I hypothesize that acylations co-occurrence will regulate transcription, and altered propionyl-CoA metabolism in PA will impact H4K16 acylations, and consequently transcription.
To achieve this, I will develop an experimental and computational framework for single-cell Simultaneous Transcriptome and Epigenome Profiling (sc-STEP-seq). With this approach, I will map H4K16ac/pr/bu and the transcriptome in single-cells, and integrate epigenomic and transcriptomic changes, in liver samples from PA mice. This interdisciplinary project will address a fundamental question in epigenetics: the functional relevance of histone PTMs regulated by metabolic state in single cells, advance the technology for single-cell multimodal epigenomic profiling, and provide for the first-time molecular understanding of histone acylations in a clinically relevant model.
Through this project, I will generate the first genome-wide histone acylation map in single cells, functionally link their co-occurrence with gene expression, and establish the impact of a metabolic disease on histone acylations and transcription. Our preliminary data showed that histone H4K16ac/pr/bu play key roles in chromatin activity and could thus regulate transcription, and are impaired in livers of a PA mouse model. I hypothesize that acylations co-occurrence will regulate transcription, and altered propionyl-CoA metabolism in PA will impact H4K16 acylations, and consequently transcription.
To achieve this, I will develop an experimental and computational framework for single-cell Simultaneous Transcriptome and Epigenome Profiling (sc-STEP-seq). With this approach, I will map H4K16ac/pr/bu and the transcriptome in single-cells, and integrate epigenomic and transcriptomic changes, in liver samples from PA mice. This interdisciplinary project will address a fundamental question in epigenetics: the functional relevance of histone PTMs regulated by metabolic state in single cells, advance the technology for single-cell multimodal epigenomic profiling, and provide for the first-time molecular understanding of histone acylations in a clinically relevant model.
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| Web resources: | https://cordis.europa.eu/project/id/101149591 |
| Start date: | 01-07-2025 |
| End date: | 30-06-2027 |
| Total budget - Public funding: | - 173 847,00 Euro |
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Original description
Regulation of transcription is orchestrated by a complex combination of histone posttranslational modifications (PTMs), but how their co-occurrence in the same cell regulate gene expression is still poorly understood. Recently, novel histone acylations have been identified, namely propionylation (pr) and butyrylation (bu). They co-exist with acetylation (ac), arise from cellular metabolism, and are key candidates to fine-tune chromatin activity and transcription. This project will answer fundamental questions on the role of acylations in gene regulation and their co-occurrence in single cells, and provide novel insights into metabolic disorders (propionic acidemia; PA), where histone acylations are altered.Through this project, I will generate the first genome-wide histone acylation map in single cells, functionally link their co-occurrence with gene expression, and establish the impact of a metabolic disease on histone acylations and transcription. Our preliminary data showed that histone H4K16ac/pr/bu play key roles in chromatin activity and could thus regulate transcription, and are impaired in livers of a PA mouse model. I hypothesize that acylations co-occurrence will regulate transcription, and altered propionyl-CoA metabolism in PA will impact H4K16 acylations, and consequently transcription.
To achieve this, I will develop an experimental and computational framework for single-cell Simultaneous Transcriptome and Epigenome Profiling (sc-STEP-seq). With this approach, I will map H4K16ac/pr/bu and the transcriptome in single-cells, and integrate epigenomic and transcriptomic changes, in liver samples from PA mice. This interdisciplinary project will address a fundamental question in epigenetics: the functional relevance of histone PTMs regulated by metabolic state in single cells, advance the technology for single-cell multimodal epigenomic profiling, and provide for the first-time molecular understanding of histone acylations in a clinically relevant model.
Status
SIGNEDCall topic
HORIZON-MSCA-2023-PF-01-01Update Date
25-11-2024
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