Descripción del proyecto
El papel de los modificadores epigenéticos en la determinación del destino celular
El conocimiento de la dinámica transcripcional que subyace a la especificación del linaje celular ha aumentado de forma considerable gracias a la secuenciación del ARN de célula única. Si bien los modificadores epigenéticos desempeñan un papel importante, aún no se comprende bien cómo guían este proceso tan dinámico. El equipo del proyecto EpiDevoTimeMachine, que cuenta con el apoyo de las Acciones Marie Skłodowska-Curie, proporcionará nueva información sobre el papel de los modificadores epigenéticos en la determinación del destino celular, lo que tendrá repercusiones de calado en la comprensión de la regulación del desarrollo en mamíferos. En concreto, se investigará la dinámica combinada y las interdenpedencias de la transcripción y el grupo de proteínas del grupo Polycomb durante la diferenciación de células madre embrionarias murinas en gastruloides.
Objetivo
During development, a cell's fate will become increasingly restricted, facilitated by the combined activity of transcription factors and epigenetic modifiers. Single-cell RNA sequencing has greatly improved our appreciation of the transcriptional dynamics underlying lineage specification. However, we still do not fully comprehend how epigenetic modifiers guide this highly dynamic process, as methods that enable us to accurately concatenate a cell's past and present epigenetic state with its current lineage identity are missing.
Here, I propose to investigate the combined dynamics and interdependencies of transcription and the polycomb-group of proteins during the differentiation of mouse embryonic stem cells into gastruloids. First, I aim to deploy a protocol that enables the simultaneous quantification of both layers in the same single cell to disentangle epigenetic from transcriptional heterogeneity. Second, I aim to develop a molecular memory system to record the past epigenetic profiles of single cells. This system will be based on the expression of proteins fused to a bacterial Dcm methylase, which will allow for the timed recording and faithful transmission of historic epigenetic profiles. Combined with quantification of transcription of the same single cell, this will enable us to directly integrate past epigenetic states with the current identity of single cells.
The proposed work here will therefore allow us to directly assess the role of epigenetic modifiers on establishing cell fate choice and will have important implications on our understanding of the regulation of mammalian development.
Ámbito científico
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
1011 JV AMSTERDAM
Países Bajos