TASOR expression in naive embryonic stem cells safeguards their developmental potential

Cell Rep. 2024 Nov 26;43(11):114887. doi: 10.1016/j.celrep.2024.114887. Epub 2024 Oct 24.

Abstract

The seamless transition through stages of pluripotency relies on a balance between transcription factor networks and epigenetic mechanisms. Here, we reveal the crucial role of the transgene activation suppressor (TASOR), a component of the human silencing hub (HUSH) complex, in maintaining cell viability during the transition from naive to primed pluripotency. TASOR loss in naive pluripotent stem cells (PSCs) triggers replication stress, disrupts H3K9me3 heterochromatin, and impairs silencing of LINE-1 (L1) transposable elements, with more severe effects in primed PSCs. Notably, the survival of Tasor knockout PSCs during this transition can be restored by inhibiting caspase or deleting the mitochondrial antiviral signaling protein (MAVS). This suggests that unscheduled L1 expression activates an innate immune response, leading to cell death specifically in cells exiting naive pluripotency. Our findings highlight the importance of epigenetic programs established in naive pluripotency for normal development.

Keywords: 5mC; CP: Stem cell research; DNA methylation; H3K9me3; HUSH complex; L1; LINE-1; Stem cells; TASOR; heterochromatin; naive pluripotency; primed pluripotency.

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Survival
  • Embryonic Stem Cells* / cytology
  • Embryonic Stem Cells* / metabolism
  • Epigenesis, Genetic
  • Humans
  • Long Interspersed Nucleotide Elements
  • Mice
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism