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  Inactivation of Lsd1 triggers senscence in trophoblast stem cells by induction of Sirt4

Castex, J., Willmann, D., Kanouni, T., Arrigoni, L., Li, Y., Friedrich, M., et al. (2017). Inactivation of Lsd1 triggers senscence in trophoblast stem cells by induction of Sirt4. Cell Death and Disease, 8, e2631-e2361. doi:10.1038/cddis.2017.48.

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Item Permalink: https://hdl.handle.net/11858/00-001M-0000-002E-8572-7 Version Permalink: https://hdl.handle.net/21.11116/0000-0008-99BA-A
Genre: Journal Article

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https://www.nature.com/articles/cddis201748 (Publisher version)
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 Creators:
Castex, Josefina1, Author
Willmann, Dominica1, Author
Kanouni, Toufike1, Author
Arrigoni, Laura2, Author
Li, Yan1, Author
Friedrich, Marcel1, Author
Schleicher, Michael1, Author
Wöhrle, Simon1, Author
Pearson, Mark1, Author
Kraut, Norbert1, Author
Méret, Michaël1, Author
Manke, Thomas2, Author
Metzger, Eric1, Author
Schüle, Roland1, Author
Günther, Thomas1, Author
Affiliations:
1External Organizations, ou_persistent22              
2Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, 79108 Freiburg, DE, ou_2243640              

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 Abstract: Coordination of energy metabolism is essential for homeostasis of stem cells, whereas an imbalance in energy homeostasis causes disease and accelerated aging. Here we show that deletion or enzymatic inactivation of lysine-specific demethylase 1 (Lsd1) triggers senescence in trophoblast stem cells (TSCs). Genome-wide transcriptional profiling of TSCs following Lsd1 inhibition shows gene set enrichment of aging and metabolic pathways. Consistently, global metabolomic and phenotypic analyses disclose an unbalanced redox status, decreased glutamine anaplerosis and mitochondrial function. Loss of homeostasis is caused by increased expression of sirtuin 4 (Sirt4), a Lsd1-repressed direct target gene. Accordingly, Sirt4 overexpression in wild-type TSCs recapitulates the senescence phenotype initiated by Lsd1 deletion or inhibition. Inversely, absence of Lsd1 enzymatic activity concomitant with knockdown of Sirt4 reestablishes normal glutamine anaplerosis, redox balance and mitochondrial function. In conclusion, by repression of Sirt4, Lsd1 directs the epigenetic control of TSC immortality via maintenance of metabolic flexibility.

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Language(s): eng - English
 Dates: 2017-02-23
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/cddis.2017.48
 Degree: -

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Title: Cell Death and Disease
  Abbreviation : Cell Death Dis
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 8 Sequence Number: - Start / End Page: e2631 - e2361 Identifier: Other: 2041-4889
CoNE: https://pure.mpg.de/cone/journals/resource/20414889