Identification of enhancer chromatin signatures involved in dopaminergic induction through multi-omics analysis

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Abstract The establishment of precise transcriptional programs during neuronal development depends on a complex and dynamic landscape of regulatory elements. Here, we combined histone modification ChIP-seq, chromatin accessibility profiling, and transcriptomics to map active enhancer repertoires during the differentiation of human embryonic stem cells into midbrain dopaminergic neurons. Our integrative analysis revealed thousands of stage-specific enhancers, over half of which were previously unannotated, and uncovered coordinated chromatin and transcriptional transitions linking pluripotency exit to neuronal lineage commitment. Functional enrichment of enhancer-linked target genes delineated distinct regulatory programs, pluripotency maintenance in undifferentiated cells and midbrain specification in differentiated neuron, while transcription factor motif analysis identified regulatory modules, including a dopaminergic-specific RFX4 network. We further characterized enhancer-gene relationships showing concordant changes in chromatin state and expression for neuronal genes, suggesting enhancer-driven control of dopaminergic identity. These findings provide a genome-scale framework for interpreting how dynamic enhancer landscapes encode developmental fate decisions in the human nervous system.

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