Dynamic lineage priming is driven via direct enhancer regulation by ERK
| العنوان: | Dynamic lineage priming is driven via direct enhancer regulation by ERK |
|---|---|
| المؤلفون: | Joshua M. Brickman, Teresa E. Knudsen, Yaron Mosesson, Kristina B. Emdal, Rita S. Monteiro, Naama Barkai, Chiara Francavilla, William B. Hamilton, Jesper V. Olsen |
| المصدر: | Hamilton, W B, Mosesson, Y, Monteiro, R S, Emdal, K B, Knudsen, T E, Francavilla, C, Barkai, N, Olsen, J V & Brickman, J M 2019, ' Dynamic lineage priming is driven via direct enhancer regulation by ERK ', Nature, vol. 575, pp. 355-360 . https://doi.org/10.1038/s41586-019-1732-z Hamilton, W B, Mosesson, Y, Monteiro, R S, Emdal, K B, Knudsen, T E, Francavilla, C, Barkai, N, Olsen, J V & Brickman, J M 2019, ' Dynamic lineage priming is driven via direct enhancer regulation by ERK ', Nature, vol. 575, no. 7782, pp. 355-360 . https://doi.org/10.1038/s41586-019-1732-z |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | MAPK/ERK pathway, 0303 health sciences, Multidisciplinary, biology, Chemistry, RNA polymerase II, Cell biology, 03 medical and health sciences, Paracrine signalling, 0302 clinical medicine, Mediator, Transcription (biology), Transcriptional regulation, biology.protein, Enhancer, Transcription factor, 030217 neurology & neurosurgery, 030304 developmental biology |
| الوصف: | Central to understanding cellular behaviour in multi-cellular organisms is the question of how a cell exits one transcriptional state to adopt and eventually become committed to another. Fibroblast growth factor-extracellular signal-regulated kinase (FGF -ERK) signalling drives differentiation of mouse embryonic stem cells (ES cells) and pre-implantation embryos towards primitive endoderm, and inhibiting ERK supports ES cell self-renewal1. Paracrine FGF–ERK signalling induces heterogeneity, whereby cells reversibly progress from pluripotency towards primitive endoderm while retaining their capacity to re-enter self-renewal2. Here we find that ERK reversibly regulates transcription in ES cells by directly affecting enhancer activity without requiring a change in transcription factor binding. ERK triggers the reversible association and disassociation of RNA polymerase II and associated co-factors from genes and enhancers with the mediator component MED24 having an essential role in ERK-dependent transcriptional regulation. Though the binding of mediator components responds directly to signalling, the persistent binding of pluripotency factors to both induced and repressed genes marks them for activation and/or reactivation in response to fluctuations in ERK activity. Among the repressed genes are several core components of the pluripotency network that act to drive their own expression and maintain the ES cell state; if their binding is lost, the ability to reactivate transcription is compromised. Thus, as long as transcription factor occupancy is maintained, so is plasticity, enabling cells to distinguish between transient and sustained signals. If ERK signalling persists, pluripotency transcription factor levels are reduced by protein turnover and irreversible gene silencing and commitment can occur. ERK reversibly regulates embryonic stem cell transcription via selective redistribution of co-factors and RNA polymerase from pluripotency to early differentiation enhancers, while leaving transcription factors bound to their enhancers, thus preserving plasticity. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0bfaa5add7d8c6570d404b0c4e9f23e0 https://curis.ku.dk/portal/da/publications/dynamic-lineage-priming-is-driven-via-direct-enhancer-regulation-by-erk(440bb80d-9602-46ab-9d10-6d00f67cbd8c).html |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....0bfaa5add7d8c6570d404b0c4e9f23e0 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |