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Telomere dysfunction cooperates with epigenetic alterations to impair murine embryonic stem cell fate commitment

Mélanie Criqui1, Aditi Qamra2, Tsz Wai Chu1

  • 1Institut de Recherche en Immunologie et Cancérologie (IRIC), Département de biologie moléculaire, Faculté de Médecine, Université de Montréal, Montréal, Canada.

Elife
|April 17, 2020
PubMed

Insights

Telomere dysfunction in stem cells alters chromatin and gene expression, impacting differentiation. Inhibiting epigenetic modifiers revealed an interdependent relationship between H3K27me3 and telomere integrity.

Area of Science:

  • Epigenetics
  • Stem Cell Biology
  • Genomics

Background:

  • The link between epigenetic changes and telomere dysfunction remains unclear.
  • Previous work demonstrated telomere erosion causes differentiation instability in murine embryonic stem cells (mESCs) via DNA hypomethylation.
  • Pluripotency factors are crucial for maintaining stem cell identity and differentiation potential.

Purpose of the Study:

  • To investigate the role of telomerase reverse transcriptase (Tert) in epigenetic regulation during stem cell differentiation.
  • To explore the impact of telomere dysfunction on chromatin accessibility and gene expression.
  • To elucidate the relationship between H3K27 trimethylation and telomere integrity in stem cell lineage commitment.

Main Methods:

  • Utilized telomerase reverse transcriptase null (Tert) mESCs to model telomere dysfunction.
  • Analyzed genome-wide chromatin accessibility and gene expression changes during differentiation.
  • Investigated the role of Polycomb Repressive Complex 2 (PRC2) and H3K27me3 demethylation using specific inhibitors.
  • Assessed stem cell differentiation capacity and pluripotency gene expression.

Main Results:

  • Tert mESCs exhibited genome-wide chromatin and gene expression alterations during differentiation.
  • An increase in H3K27me3 globally and altered chromatin at the Pou5f1/Oct4 promoter were observed in Tert mESCs.
  • Tert mESCs showed impaired differentiation and refractory response to differentiation cues.
  • PRC2 inhibition worsened differentiation defects in Tert mESCs, while H3K27me3 demethylation inhibition partially rescued the phenotype.

Conclusions:

  • Telomere dysfunction induces significant epigenetic alterations, including changes in H3K27me3, affecting stem cell differentiation.
  • A novel interdependent relationship exists between H3K27me3 and telomere integrity in regulating stem cell lineage commitment.
  • These findings have potential implications for understanding aging and cancer development.
Keywords:
cell differentiationchromosomesembryonic stem cellsepigeneticsgene expressionmousetelomerase reverse transcriptasetelomeres

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