SubsidieMeestersRibosome Heterogeneity as a Determinant of Cellular Identity in Hematopoiesis and Leukemia
This project aims to investigate how ribosome heterogeneity influences cell-type-specific translation and differentiation in hematopoiesis and leukemia, revealing new gene regulation mechanisms.
Projectdetails
Introduction
Differentiation and acquisition of cell identity are fundamental processes in multi-cellular organisms. It is well established that chromatin and RNA mechanisms regulate cell fate determination. Mounting evidence from our lab and others, however, suggests that translation is an additional, until now underappreciated, determinant of cell fate.
Importance of Translation
The importance of translation to differentiation can be gleaned from the hematopoietic system, where a prominent feature of human congenital syndromes, due to mutated ribosomes, is aberrant blood production. Crucially, these mutations lead to distinct cell-type-specific differentiation defects, rather than systemic failure.
Research Question
It remains unclear how congenital (“total-body”) ribosomal mutations only affect particular differentiation paths and manifest in a cell-type-specific fashion. We hypothesize that cell-type-specific ribosomal composition—i.e., ribosome heterogeneity—results in cell-type-specific translation profiles, and therefore represents a crucial layer of gene regulation in cell fate and differentiation.
Objectives
We will explore this hypothesis by pursuing three complementary objectives:
- Systematically map ribosome heterogeneity and reveal its function in normal hematopoiesis and leukemia.
- Determine how ribosome heterogeneity controls cell-type-specific translatomes and contributes to cellular transformation.
- Explore ribosome heterogeneity at single-cell resolution, using novel methodologies we will develop for simultaneous transcription and translatome interrogation.
Methodology
By combining cutting-edge sequencing techniques with extensive genetic manipulations in physiological settings, we will reveal cell-type-specific translation, controlled by cell-type-specific ribosomes, as major regulators of cell fate in health and disease.
Conclusion
Understanding the mechanisms of cell-type-specific translation will provide a new paradigm for elucidating gene expression regulation and for revealing new mechanisms for human diseases.
Financiële details & Tijdlijn
Financiële details
| Subsidiebedrag | € 1.700.000 |
| Totale projectbegroting | € 1.700.000 |
Tijdlijn
| Startdatum | 1-10-2023 |
| Einddatum | 30-9-2028 |
| Subsidiejaar | 2023 |
Partners & Locaties
Projectpartners
- THE HEBREW UNIVERSITY OF JERUSALEMpenvoerder
Land(en)
Vergelijkbare projecten binnen European Research Council
| Project | Regeling | Bedrag | Jaar | Actie |
|---|---|---|---|---|
Unraveling Ribosome Heterogeneity: Implications for Metastasis and BeyondThis project aims to map ribosomal heterogeneity in metastatic cancers to uncover how specialized ribosomes influence oncogenic translation and metastasis, potentially identifying new cancer biomarkers and therapies. | ERC Starting... | € 1.500.000 | 2025 | Details |
Development of novel integrated sequencing methods to explore translation and its regulatory mechanisms in single cellsThis project aims to develop novel multi-omics approaches to quantify translation in single cells, integrating various regulatory mechanisms to enhance understanding of cellular heterogeneity. | ERC Advanced... | € 2.500.000 | 2023 | Details |
Translational specialization of cellular identity in embryonic development and diseaseTRANSCEND aims to explore how translational specialization factors influence cell-fate decisions in embryogenesis, with a focus on cardiac identity and therapeutic restoration of cardiac function. | ERC Consolid... | € 1.981.555 | 2023 | Details |
Uncovering the Diversity of Cell-Cell Interactions that Impact Cell FatesThis project aims to develop a novel method for high-resolution transcriptomic analysis of cellular microenvironments to understand how cell communication influences neural crest cell development and fate. | ERC Starting... | € 1.499.900 | 2023 | Details |
Elucidating the interplay between nuclear compartments and transcriptional dynamics during differentiationDynaDiff aims to explore the role of membraneless organelles in transcriptional regulation during mammalian differentiation using advanced single-cell RNA sequencing techniques. | ERC Starting... | € 1.498.372 | 2022 | Details |
Unraveling Ribosome Heterogeneity: Implications for Metastasis and Beyond
This project aims to map ribosomal heterogeneity in metastatic cancers to uncover how specialized ribosomes influence oncogenic translation and metastasis, potentially identifying new cancer biomarkers and therapies.
Development of novel integrated sequencing methods to explore translation and its regulatory mechanisms in single cells
This project aims to develop novel multi-omics approaches to quantify translation in single cells, integrating various regulatory mechanisms to enhance understanding of cellular heterogeneity.
Translational specialization of cellular identity in embryonic development and disease
TRANSCEND aims to explore how translational specialization factors influence cell-fate decisions in embryogenesis, with a focus on cardiac identity and therapeutic restoration of cardiac function.
Uncovering the Diversity of Cell-Cell Interactions that Impact Cell Fates
This project aims to develop a novel method for high-resolution transcriptomic analysis of cellular microenvironments to understand how cell communication influences neural crest cell development and fate.
Elucidating the interplay between nuclear compartments and transcriptional dynamics during differentiation
DynaDiff aims to explore the role of membraneless organelles in transcriptional regulation during mammalian differentiation using advanced single-cell RNA sequencing techniques.