Objetivo
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.
Ámbito científico (EuroSciVoc)
CORDIS clasifica los proyectos con EuroSciVoc, una taxonomía plurilingüe de ámbitos científicos, mediante un proceso semiautomático basado en técnicas de procesamiento del lenguaje natural.
CORDIS clasifica los proyectos con EuroSciVoc, una taxonomía plurilingüe de ámbitos científicos, mediante un proceso semiautomático basado en técnicas de procesamiento del lenguaje natural.
Para utilizar esta función, debe iniciar sesión o registrarse
Palabras clave
Programa(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régimen de financiación
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinador
85764 Neuherberg
Alemania