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β-Hydroxybutyrate promotes dopaminergic induction via H3K27ac remodeling in human midbrain organoids [RNA-seq]

ABSTRACT: Neuronal differentiation relies on tightly regulated transcriptional programs driven by morphogens, yet the role of physiologically derived metabolites in development remains poorly understood. Here, we investigated the effect of the ketone body β-hydroxybutyrate on dopaminergic differentiation using midbrain organoids derived from human embryonic stem cells. Treatment with 1 mM β-hydroxybutyrate for 16 days significantly increased the number of TH⁺ dopaminergic neurons. Transcriptomic analysis by RNA-seq at days 8 and 16 revealed the enrichment of neuronal and dopamine-associated genes, while CUT&RUN profiling of H3K27ac uncovered widespread epigenomic remodeling at neural and dopaminergic regulatory regions. Motif and clustering analyses identified stage-specific enhancer groups, including a day 16-enriched cluster containing validated GeneHancer elements with predicted LMX1B and FOXA2 binding sites. Integration of predicting transcriptional factor binding motifs, and RNAseq data and enrichment H3K27ac enabled the construction of gene regulatory networks using our custom web platform, Enhancer Network Explorer. Together, our results demonstrate that β-hydroxybutyrate reshapes the epigenomic landscape to promote dopaminergic differentiation, suggesting that ketone bodies plays a role in human brain development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313206 | GEO | 2026/08/31

REPOSITORIES: GEO

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β-Hydroxybutyrate promotes dopaminergic induction via H3K27ac remodeling in human midbrain organoids [CUT&Run]

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