Dissecting and Perturbing Epigenetic Regulation in Human Cerebral Organoids

• Applicant: Boyan Bonev, Ph.D.
• Subject Area: Developmental Neurobiology ; General Genetics and Functional Genome Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563413215

The human cerebral cortex emerges from a precisely orchestrated interplay between gene regulation, epigenomic states, and environmental cues. Yet, the mechanisms by which epigenetic regulators shape cellular identity, respond to changing signals, and guide the progressive specification of diverse neuronal subtypes remain unclear. Our laboratory has established a strong foundation in epigenomics, single-cell multi-omics, and human cerebral organoid models, enabling us to tackle these fundamental questions with unprecedented depth and resolution. Building upon this expertise, we will dissect how epigenetic regulation informs cell fate decisions and adapts to dynamic signaling environments during human brain development. We will use a comprehensive, temporally resolved approach to: 1) identify critical epigenetic factors, 2) determine how they remodel chromatin architecture and regulatory landscapes, and 3) reveal how their activity responds to altered signaling states. Leveraging innovative single-cell perturbation strategies and multi-modal epigenomic profiling, we will pinpoint the mechanisms that enable these regulators to integrate temporal and environmental cues, ultimately influencing lineage specification and neuronal maturation. By generating mechanistic insights into the interplay between epigenetic regulation, gene expression, and the evolving cellular context, our work will address longstanding challenges in developmental neurobiology and epigenetics. The conceptual frameworks and methodologies we develop—ranging from high-throughput functional assays to integrative computational analyses—will benefit the Priority Program and the broader research community. They will inform the study of neurodevelopmental disorders linked to epigenetic dysregulation, enhance our ability to define and manipulate cellular identities, and complement the consortium’s collective efforts to understand epigenome adaptation in the developing human brain.

• DFG Programme: Priority Programmes
• Subproject of: SPP 2502: EPIADAPT: Epigenomic adaptations of the developing neural chromatin