Telomere dysfunction cooperates with epigenetic alterations to impair murine embryonic stem cell fate commitment
Mélanie Criqui,
Aditi Qamra,
Tsz Wai Chu,
Monika Sharma,
Julissa Tsao,
Danielle A Henry,
Dalia Barsyte-Lovejoy,
Cheryl H Arrowsmith,
Neil Winegarden,
Mathieu Lupien,
Lea Harrington
Affiliations
Mélanie Criqui
Institut de Recherche en Immunologie et Cancérologie (IRIC), Département de biologie moléculaire, Faculté de Médecine, Université de Montréal, Montréal, Canada
Aditi Qamra
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
Tsz Wai Chu
Institut de Recherche en Immunologie et Cancérologie (IRIC), Département de biologie moléculaire, Faculté de Médecine, Université de Montréal, Montréal, Canada
Monika Sharma
Princess Margaret Genomics Centre, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
Julissa Tsao
Princess Margaret Genomics Centre, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
Danielle A Henry
Institut de Recherche en Immunologie et Cancérologie (IRIC), Département de biologie moléculaire, Faculté de Médecine, Université de Montréal, Montréal, Canada
Dalia Barsyte-Lovejoy
Structural Genomics Consortium, Princess Margaret Cancer Centre, University of Toronto, Department of Medical Biophysics, Toronto, Canada
Cheryl H Arrowsmith
Structural Genomics Consortium, Princess Margaret Cancer Centre, University of Toronto, Department of Medical Biophysics, Toronto, Canada
Neil Winegarden
Princess Margaret Genomics Centre, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
Institut de Recherche en Immunologie et Cancérologie (IRIC), Département de biologie moléculaire, Faculté de Médecine, Université de Montréal, Montréal, Canada
The precise relationship between epigenetic alterations and telomere dysfunction is still an extant question. Previously, we showed that eroded telomeres lead to differentiation instability in murine embryonic stem cells (mESCs) via DNA hypomethylation at pluripotency-factor promoters. Here, we uncovered that telomerase reverse transcriptase null (Tert-/-) mESCs exhibit genome-wide alterations in chromatin accessibility and gene expression during differentiation. These changes were accompanied by an increase of H3K27me3 globally, an altered chromatin landscape at the Pou5f1/Oct4 promoter, and a refractory response to differentiation cues. Inhibition of the Polycomb Repressive Complex 2 (PRC2), an H3K27 tri-methyltransferase, exacerbated the impairment in differentiation and pluripotency gene repression in Tert-/- mESCs but not wild-type mESCs, whereas inhibition of H3K27me3 demethylation led to a partial rescue of the Tert-/- phenotype. These data reveal a new interdependent relationship between H3K27me3 and telomere integrity in stem cell lineage commitment that may have implications in aging and cancer.
