Spatiotemporal Tracking of Human Neurodevelopmental Imprinting with Cerebral Organoids | AIChE

Spatiotemporal Tracking of Human Neurodevelopmental Imprinting with Cerebral Organoids


Sen, D. - Presenter, North Carolina State University
Keung, A., North Carolina State University
Epigenetic mechanisms play essential roles in mammalian neurodevelopment. Genomic imprinting is a process causing the mono-allelic expression of a gene in a parental origin specific manner, and it is controlled by a hierarchy of epigenetic events. Although they are small in number, many imprinted genes are expressed in the human brain and hold important roles in development and disease. As a key example, the imprinted gene UBE3A is an important nexus in neurodevelopment and complex brain disorders where deletion of the maternal or paternal alleles of UBE3A differentially leads to Angelman Syndrome or Prader-Willi Syndrome, respectively. In addition, duplication of maternal UBE3A occurs in some forms of Autism Spectrum Disorder. These three diseases share some common neurological comorbidities strongly suggesting UBE3A’s role in neural function; yet, it is still unclear when, where, and how UBE3A is regulating or disrupting normal neurodevelopment or adult brain function. Therefore, mapping the allelic specificity and subcellular localization of UBE3A expression in neurons and other cell types in the brain could provide key insights into the underlying mechanisms of UBE3A-related disorders and suggest key cell types and brain regions for further study. However, due to technical and ethical limitations, such maps have yet to be generated in humans. Here we aim to map maternal and paternal allele-specific UBE3A expression throughout early prenatal brain development by engineering human cerebral organoids with allele-specific fluorescent reporters. Human cerebral organoids are model systems that exhibit most cell types of the human brain as well as polarized tissue structures, and have been temporally correlated with early fetal neurodevelopment. Through this human system, we connect molecular epigenetic processes to tissue-level properties by spatiotemporally mapping UBE3A imprinting events. This map suggests several specific brain regions, cell types, developmental time windows, and mechanistic hypotheses to pursue in understanding UBE3A’s role in the human brain and in neurodevelopmental disorders.