Project description
Advanced study into the mechanisms of transcriptional memory
Transcriptional memory is a phenomenon during which cells primed with particular stimuli show increased gene expression after re-stimulation at a later time. Such memory of gene expression states is essential for the development and maintenance of tissues. Funded by the Marie Skłodowska-Curie Actions programme, the IMMUNE-GENEMEMO project is based on the discovery of genes with a strong transcriptional memory of prior interferon-gamma (IFNγ) activation, creating a larger proportion of cells expressing the target gene. The project aims to identify novel transcriptional memory maintenance factors in human cells using an efficient high-throughput cell sorting strategy combined with genome-wide CRISPR-Cas9 mutagenesis protocols, and establish the role of these components in the stability of dendritic cell identity.
Objective
Memory of gene expression states is essential for development and maintenance of tissues. Chromatin, a protein DNA complex, is implicated in the process. Local, chromatin feedback loops are involved in maintenance of gene silencing, but analogous mechanisms for preservation of active states are unknown. In order to reveal feedback loops for active gene expression states it is crucial to uncouple them from ongoing transcription, as it occurs in the case of maintenance of silent states. Such partition takes place during trained immunity – memory of the innate immune system. A key paradigm is interferon gamma (IFNγ) stimulation. While IFNγ induces many genes, a subset of those is maintained in a poised, inactive state that allows for rapid re-activation at a later time – an event called transcriptional memory.
In my ongoing research I have discovered novel genes that show strong transcriptional memory of prior IFNγ activation and have obtained initial mechanistic insights into the role of chromatin in the process. Importantly, I discovered that memory results in a larger proportion of cells expressing the target gene. This forms the basis of a cell sorting, high throughput assay that I have developed. I am now in a unique position to capitalize on those discoveries and tools.
I aim to identify novel transcriptional memory maintenance factors in human cells using an unbiased approach based on an efficient cell selection strategy combined with genome wide, CRISPR-Cas9 mutagenesis protocols. Secondly I wish to establish the function of the identified components in the stability of dendritic cells identity after differentiation form monocytes.
The multidisciplinary and unique perspective of this project: combining gene expression analysis and selection strategies with immunological expertise will advance our understanding of the mechanisms underlying maintenance of gene expression states and contribute to the development of new immune therapies and vaccines.
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Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
80-309 GDANSK
Poland