IMMUNE-GENEMEMO · Identification of transcriptional memory maintenance factors through a cell selection strategy
„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“
- Период
- 2021-06-01 → 2024-05-31
- Финансиране от ЕС
- 252 079 €
- Участници
- 2
- Схема
- MSCA-IF
Линиите свързват координатора с партньорите.
Накратко на български
Транскрипционната памет позволява на имунните клетки да реагират по-бързо и силно при повторна среща с определен сигнал. Разбирането на тези молекулярни механизми помага за по-доброто управление на имунната система с цел подобряване на общественото здраве.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Identification of transcriptional memory maintenance factors through a cell selection strategy
Cellular memory of gene expression states is essential for development and maintenance of tissues and hence for human health. How this process is controlled on a molecular level is not fully understood. Here we study the phenomenon of innate immune memory, specifically transcriptional memory, to gain new insights into maintenance mechanisms of gene expression states. Transcriptional memory is a biological process during which cells induced with a particular signal display increased rates of gene expression after re-stimulation at a later stage. In this project, I use an unbiased genetic strategy to identify novel transcriptional memory regulatory factors to understand the molecular mechanisms of the phenomenon. I next generalize the discovered knowledge to the biology of innate immune cells. This project empowers me to establish myself as a scientific leader in the field. Insights from this research uncover new gene regulatory mechanisms and pave the way for manipulation of the innate immune system for the benefit of public health. In conclusion, in this project we discovered a novel mechanism of transcriptional memory that we published in the EMBO journal. Additionally, by performing a genetic screen we paved the way for future discoveries and translation to a clinical setting. Moreover, we extended the observations to other cell types. Aside from that, we tested several mechanistic hypothesis. In addition, I promoted the results of this action as an invited speaker at Harvard Medical School and the University of Gdansk, but also during two outreach activities that I organized. As a consequence of this action, I was able to secure an associate professor position at the University of Gdansk, together with independent funding to continue this research.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
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.
Оригинален текст от CORDIS (на английски).
Участници
- UNIWERSYTET GDANSKI · GDANSKКоординаторПолша
- THE GENERAL HOSPITAL CORPORATION · BOSTON MAСъединени щати
Връзки
Данни: CORDIS, © Европейски съюз