Highlights d TAM efficiently modulates four types of splicing in their native genomic context d Genetic modulation of RNA splicing elucidates functions of splicing isoforms d TAM enables both loss-and gain-of-function studies of splicing events d TAM corrects the open reading frame of 99.9% of DMD transcripts in patient iPSCs

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Highlights d Slc16a11 knockout mice have minimal metabolic consequences d Mice carrying SLC16A11 mutations have disrupted lipid metabolism and fatty liver d Mutant SLC16A11 upregulates lipin 1 and increases liver triglyceride accumulation

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SummaryHepatocyte-like cells (HLCs) derived from human pluripotent stem cells (hPSCs) offer a promising cell resource for disease modeling and transplantation. However, differentiated HLCs exhibit an immature phenotype and comprise a heterogeneous population. Thus, a better understanding of HLC differentiation will improve the likelihood of future application. Here, by taking advantage of CRISPR-Cas9-based genome-wide screening technology and a high-throughput hPSC screening platform with a reporter readout, we identified several potential genetic regulators of HLC differentiation. By using a chemical screening approach within our platform, we also identified compounds that can further promote HLC differentiation and preserve the characteristics of in vitro cultured primary hepatocytes. Remarkably, both screenings identified histone deacetylase 3 (HDAC3) as a key regulator in hepatic differentiation. Mechanistically, HDAC3 formed a complex with liver transcriptional factors, e.g., HNF4, and co-regulated the transcriptional program during hepatic differentiation. This study highlights a broadly useful approach for studying and optimizing hPSC differentiation.

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