Laboratory for Advanced Genomics Circuit, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan

Institute for Pharmaceutical Sciences, ETH Zürich, Switzerland

At least one billion people worldwide are affected by neurological disorders irrespective of gender, age, or education. However, effective treatment is poor due to the lack of molecular understanding of the disease. Emerging evidence has shown that non-coding regulatory elements (NCRE) such as enhancers and promoters play an essential role in controlling neural development and triggering a wide range of neurological disorders including Alzheimer’s and Parkinson’s diseases. Investigating gene regulation mediated by NCRE is therefore the most fundamental component to modulate neural growth and reduction in the human brain.  The differentiation of human pluripotent stem cells into 3-dimensional cerebral organoids offers an unprecedented opportunity to address these fundamental questions. Using human iPS cells from a healthy individual, we successfully established cerebral organoids and performed 5′-based bulk CAGE seq at six distinctive developmental stages. Our results reveal the importance of non-coding RNAs, including enhancer RNAs, in governing brain development in a time-dependent manner. To further elucidate cellular heterogeneity and dynamic gene expression, we combined bulk CAGE with single cell 5′-RNA-seq to identify “developmental eRNAs” in specific compartments of cerebral organoids.  We plan to systematically perturb developmental eRNAs to extrapolate causative factors for neuro-regeneration and -degeneration in our aging population.