As a developmental neurobiology PhD candidate analyzing chromatin regulation in human brain development, I seek to join the Hong Kong Laureate Forum to engage with scientific pioneers across disciplines. My research combines cutting-edge single-cell techniques to profile human fetal brain histone modifications with computational modeling, creating a foundation for sequence-to-function prediction models. I aim to gain insights from Laureates on integrating biological understanding with advanced computational approaches, particularly promptly as AI reshapes scientific research methodologies. The Forum offers a unique opportunity to connect with fellow early-career scientists working at similar interdisciplinary frontiers, potentially catalyzing collaborations that bridge epigenetic regulation, neurodevelopment, and machine learning. These interactions would significantly enhance my approach to deciphering the epigenetic basis of human brain development and its implications for neurodevelopmental disorders.

The first trimester of human brain development is marked by rapid neurogenesis and cortical differentiation, driven by dynamic chromatin remodeling. While single-cell RNA sequencing (scRNA-seq) has advanced our understanding of transcriptional programs, the chromatin-based regulatory mechanisms orchestrating neuronal fate remain poorly resolved. Here, we leverage a high-resolution single-cell chromatin profiling dataset (sc-nanoCUT&Tag) to map epigenetic states across thousands of cells during early human cortical development. Focusing on histone modifications H3K27ac (active promoters or enhancers) and H3K27me3 (polycomb-repressed regions), we dissect the regulatory logic governing cell identity and differentiation trajectories. Our analysis reveals temporally resolved chromatin accessibility patterns and predicts cell type-specific regulatory elements that coordinate neurogenic transitions. Integration with transcriptomic data identifies key transcription factors linked to lineage commitment, while spatial chromatin state dynamics uncover repression of progenitor programs during neuronal maturation. Notably, we resolve epigenetic priming events preceding cellular diversification and pinpoint cross-talk between enhancer activation and polycomb-mediated silencing in cortical subtypes. This work provides the first survey of single-cell histone modification in human fetal cortical development, decoding the interplay of histone modifications in shaping neuronal diversity. Our findings illuminate fundamental principles of gene regulation during cortical neurogenesis, with implications for neurodevelopmental disorders rooted in epigenetic dysregulation.