An ERK5-KLF2 signalling module regulates early embryonic gene expression and telomere rejuvenation in stem cells

The ERK5 MAP kinase signalling pathway drives transcription of naïve pluripotency genes in mouse Embryonic Stem Cells (mESCs). However, how ERK5 impacts on other aspects of mESC biology has not been investigated. Here, we employ quantitative proteomic profiling to identify proteins whose expression...

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Detalles Bibliográficos
Autores: Brown, Helen A., Williams, Charles A.C., Zhou, Houjiang, Rios-Szwed, Diana, Fernandez-Alonso, Rosalia, Mansoor, Saria, McMulkin, Liam, Toth, Rachel, Gourlay, Robert, Peltier, Julien, Diéguez-Martínez, Nora|||0000-0002-5366-4543, Trost, Matthias, Lizcano de Vega, José Miguel|||0000-0002-3154-5383, Stavridis, Marios P., Findlay, Greg M.|||0000-0002-7222-4965
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:302985
Acceso en línea:https://ddd.uab.cat/record/302985
https://dx.doi.org/urn:doi:10.1042/BCJ20210646
Access Level:acceso abierto
Palabra clave:Embryonic stem cells
Extracellular signal-regulated kinases
Kruppel-like transcription factors
Proteomics
Descripción
Sumario:The ERK5 MAP kinase signalling pathway drives transcription of naïve pluripotency genes in mouse Embryonic Stem Cells (mESCs). However, how ERK5 impacts on other aspects of mESC biology has not been investigated. Here, we employ quantitative proteomic profiling to identify proteins whose expression is regulated by the ERK5 pathway in mESCs. This reveals a function for ERK5 signalling in regulating dynamically expressed early embryonic 2-cell stage (2C) genes including the mESC rejuvenation factor ZSCAN4. ERK5 signalling and ZSCAN4 induction in mESCs increases telomere length, a key rejuvenative process required for prolonged culture. Mechanistically, ERK5 promotes ZSCAN4 and 2C gene expression via transcription of the KLF2 pluripotency transcription factor. Surprisingly, ERK5 also directly phosphorylates KLF2 to drive ubiquitin-dependent degradation, encoding negative feedback regulation of 2C gene expression. In summary, our data identify a regulatory module whereby ERK5 kinase and transcriptional activities bi-directionally control KLF2 levels to pattern 2C gene transcription and a key mESC rejuvenation process.

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