Primate-specific endogenous retrovirus-driven transcription defines naive-like stem cells

Area of Science:

• Stem cell biology
• Genomics
• Developmental biology

Background:

• Naive embryonic stem cells (ESCs) possess broad developmental potential, crucial for research and therapeutics.
• Isolating human naive ESCs is challenging; current methods involve artificial generation of naive-like cells from primed human ESCs or induced pluripotent stem cells (hiPSCs).

Purpose of the Study:

• To identify and characterize a naturally occurring sub-population of naive-like cells within human ESC and hiPSC cultures.
• To investigate the role of primate-specific endogenous retroviruses, particularly HERVH, in regulating pluripotency in these naive-like cells.

Main Methods:

• Analysis of sub-populations within human ESC and hiPSC cultures.
• Genetic tagging of cells.
• Transcriptional profiling, focusing on HERVH and associated factors like LBP9.
• Functional studies involving disruption of key genetic elements (LBP9, HERVH).

Main Results:

• A sub-population of hESCs and hiPSCs naturally exhibits naive stem cell properties.
• Elevated HERVH transcription is a hallmark of these naive-like cells.
• HERVH elements serve as binding sites for naive pluripotency factors, including LBP9, driving unique transcripts.
• Disruption of LBP9, HERVH, or derived transcripts impairs self-renewal capacity.

Conclusions:

• HERVH expression is a defining characteristic of naive-like human ESCs.
• Novel primate-specific transcriptional circuitry involving HERVH and LBP9 regulates pluripotency and self-renewal.
• This discovery provides new insights into the regulation of pluripotency in human stem cells.