TASOR expression in naive embryonic stem cells safeguards their developmental potential

Area of Science:

• Epigenetics
• Stem Cell Biology
• Molecular Biology

Background:

• Pluripotency transitions require precise regulation of transcription factors and epigenetic mechanisms.
• The human silencing hub (HUSH) complex plays a role in maintaining genome stability.
• LINE-1 (L1) retrotransposons are mobile genetic elements that must be silenced to prevent genomic instability.

Purpose of the Study:

• To investigate the role of transgene activation suppressor (TASOR) in maintaining cell viability during the transition from naive to primed pluripotency.
• To understand the molecular mechanisms underlying cell death observed upon TASOR loss.
• To identify potential therapeutic targets for preserving stem cell function during pluripotency transitions.

Main Methods:

• Utilized pluripotent stem cells (PSCs) with and without TASOR.
• Assessed replication stress, H3K9me3 heterochromatin levels, and L1 element silencing.
• Investigated the impact of caspase inhibition and MAVS deletion on cell survival.
• Analyzed the role of innate immune signaling pathways.

Main Results:

• TASOR loss in naive PSCs induced replication stress and disrupted H3K9me3 heterochromatin.
• Impaired silencing of LINE-1 (L1) transposable elements was observed, with exacerbated effects in primed PSCs.
• Cell death in Tasor knockout PSCs exiting naive pluripotency was rescued by inhibiting caspase or deleting MAVS.
• Unscheduled L1 expression activates an innate immune response, leading to cell death.

Conclusions:

• TASOR is essential for cell viability during the transition from naive to primed pluripotency.
• Epigenetic regulation by TASOR and HUSH complex is critical for silencing L1 elements and preventing aberrant immune activation.
• The findings underscore the importance of established epigenetic programs in naive pluripotency for normal stem cell development and survival.