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Cell Death Dis. 2017 Feb 23;8(2):e2631. doi: 10.1038/cddis.2017.48.

Inactivation of Lsd1 triggers senescence in trophoblast stem cells by induction of Sirt4.

Author information

1
Urologische Klinik und Zentrale Klinische Forschung, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
2
Celgene Quanticel Research, San Diego, CA, USA.
3
Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
4
metaSysX GmbH, Potsdam-Golm, Germany.
5
Boehringer Ingelheim, Vienna, Austria.
6
Deutsches Konsortium für Translationale Krebsforschung, Standort Freiburg, Freiburg, Germany.
7
BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany.

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.

PMID:
28230862
PMCID:
PMC5386490
DOI:
10.1038/cddis.2017.48
[Indexed for MEDLINE]
Free PMC Article

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