Genetic Variation in Pluripotent Stem Cells Influences Gene Regulation in Regenerative Medicine

New research by investigators from Jackson Laboratory has found that genetic variation in pluripotent stem cells leads to phenotypic variability, challenging regenerative medicine. The study, published in G3: Genes, Genomes, Genetics, aimed to investigate how genetic variants affecting the pluripotent state influence gene regulation later in development. The researchers characterized expression of 12,000 genes in a large panel of donor-matched Diversity Outbred mouse embryonic stem cell and mouse neural progenitor cell lines.

Key Takeaways:

• The study found that local mouse neural progenitor cell expression QTLs are more likely than distant expression QTLs to be shared with mouse embryonic stem cells.
• Distant mouse neural progenitor cell expression QTLs are numerous but largely unique to that cell type, with many colocalizing to mouse neural progenitor cell-specific hotspots.
• Mediation analysis across cell types suggests that expression of Pign in mouse embryonic stem cells shapes the transcriptome of the more specialized mouse neural progenitor cell state.
• The researchers identified 4,060 expression QTLs in mouse neural progenitor cells, including 2,998 local and 1,062 distant expression QTLs.
• Rnf152 was identified as the best candidate mediator expressed in mouse neural progenitor cells.
• Genetic variant(s) affecting Pign expression in the mouse embryonic stem cell state were implicated as regulating the mouse neural progenitor cell chromosome 1 hotspot.

Statistics:

• 12,000 genes were characterized for expression in a large panel of donor-matched Diversity Outbred mouse embryonic stem cell and mouse neural progenitor cell lines.
• 4,060 expression QTLs were identified in mouse neural progenitor cells.
• 2,998 of these QTLs were local expression QTLs.
• 1,062 QTLs were distant expression QTLs.
• 3 mouse neural progenitor cell-specific expression QTL hotspots were mapped on chromosomes 1, 10, and 11.

Sources:

• Systems Genetics Reveals the Influence of Expression Qtls In Mouse Embryonic Stem Cells On Transcriptional Variation Later In Differentiated Neural Progenitor Cells. G3: Genes, Genomes, Genetics, 2025.
• Jackson Laboratory. "Findings from Jackson Laboratory Has Provided New Data on Regenerative Medicine."
• NewsRx. "Findings from Jackson Laboratory Has Provided New Data on Regenerative Medicine (Systems Genetics Reveals the Influence of Expression Qtls In Mouse Embryonic Stem Cells On Transcriptional Variation Later In Differentiated Neural Progenitor Cells)." Biotech Week. June 18, 2025; p 126.