Systems genetics reveals the influence of eQTLs in mouse embryonic stem cells on transcriptional variation later in differentiated neural progenitor cells

Genetic variation leads to phenotypic variability in pluripotent stem cells that presents challenges for regenerative medicine. Although recent studies have investigated the impact of genetic variation on pluripotency maintenance and differentiation capacity, less is known about how genetic variants affecting the pluripotent state influence gene regulation later in development. Here, we characterized expression of 12,000 genes in a large panel of donor-matched Diversity Outbred (DO) mouse embryonic stem cell (mESC) and neural progenitor cell (mNPC) lines. Quantitative trait locus (QTL) mapping identified 4,060 expression QTL (eQTL) in mNPCs, including 2,998 local and 1,062 distant eQTL. In a comparison of mNPC and mESC eQTLs, we found that local eQTLs were more likely than distant eQTL to be detected in both cell types. Distant eQTL were largely unique to one cell type, and we mapped three mNPC-specific eQTL hotspots on Chromosomes (Chrs) 1, 10, and 11. Mediation analysis of the Chr 1 hotspot identified Rnf152 as the best candidate mediator expressed in mNPCs, while cross-cell type mediation using mESC gene expression along with partial correlation analysis strongly implicated genetic variant(s) affecting Pign expression in the mESC state as regulating the mNPC Chr 1 hotspot. These findings highlight that local mNPC eQTL are more likely than distant eQTL to be shared with mESCs; distant mNPC eQTL are numerous but largely unique to that cell type, with many co-localizing to mNPC-specific hotspots; and mediation analysis across cell types suggests that expression of Pign in mESCs shapes the transcriptome of the more specialized mNPC state.