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Single-cell activation screen identifies hepatic maturation regulators with zonal resolutio

ABSTRACT: The maturation of lineage-committed embryonic hepatocytes requires timed activation of gene regulatory networks (GRNs) while silencing embryonic programs to achieve adult hepatic metabolic functions. Our knowledge of the key transcription regulators (TRs) governing the GRN rewiring during late development are still incomplete, hindering the derivation of functional hepatocytes through scalable in vitro approaches. To address this, we employed a dCas9 activation screening in combination with single cell transcriptomics on primary mouse embryonic hepatocytes followed by effect ranking among developmentally late-onset TRs. We identify Nr1i3 as a potent inducer of pericentrally expressed metabolic function-related genes and Nfix as a critical suppressor of embryonic signatures. Supplementation of liver zonation patterning signals together with these TRs enhanced the expression of pericentrally zonated Cyp genes, emphasizing the importance of a microenvironment-targeted approach for inducing maturation. Our screen and analysis highlight key regulatory mechanisms underlying organ maturation and offers general insights for improving the functionality of in vitro derived cells

ORGANISM(S): Mus musculus

PROVIDER: GSE242934 | GEO | 2025/09/05

REPOSITORIES: GEO

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