BMI Seminar // Fides Zenk - Single-cell epigenomic reconstruction of developmental trajectories in human neural organoid systems

The cell type diversity of the human body originates from just one single totipotent cell. How the different cell types emerge from the same genomic sequence and how they maintain their identities throughout development is still an open question in biology. Epigenetic modifications that can direct the activity of genes and regulatory elements during development play an important role in the process of cell identity decisions. Here, we explore how brain development and in particular, the differentiation of progenitor cells into different neuronal and glial branches is regulated by epigenetic mechanisms. We use human multiregion brain organoids to model the earliest events of cell fate acquisition in the developing brain and apply single-cell epigenetic profiling of histone modifications at various stages of brain and retina organoid development. We use this data to reconstruct the epigenetic trajectory governing cell fate acquisition. We find that switching of epigenetic modifications can precede the activation of important brain region-specific transcription factors. Further, we show that perturbation of epigenetic modifiers during neuroectoderm establishment disrupts fate decisions and leads to aberrant cell fate acquisition. This ultimately influences development and cell type composition of brain organoids. In summary, we provide the first comprehensive single-cell atlas of histone modifications during human brain organoid development, which will serve as a reference to understand early cell fate decisions and neurodevelopmental diseases associated with chromatin regulators.