Department of Biostatistics
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December 6, 2022 @ 1:00 pm - 2:00 pm
Assistant Professor of Neurobiology
Probing the single-cell 3D genome architectural basis of neurodevelopment and aging in vivo
How do cells in our nervous system develop highly specialized functions despite having (approximately) the same genome? An emerging mechanism is 3D genome architecture: the folding of our 2-meter-long genome into each 10-micron cell nucleus. This architecture brings together genes and distant regulatory elements to orchestrate gene transcription, and has been implicated in neurodevelopmental and degenerative diseases. However, genome architecture is extremely difficult to measure. I developed a DNA sequencing–based method, termed Dip-C, which solved the first 3D structure of the human genome in a single cell. Applying Dip-C to the developing mouse eye, I revealed genome-wide radial inversion of euchromatin and heterochromatin, forming a microlens to concentrate light at night. In the mouse nose, I discovered multiple inter-chromosomal hubs that contain hundreds of olfactory receptor genes and their enhancers, providing a structural basis for their “1 neuron–1 receptor” expression. In the brain, I determined the dynamics of 3 facets of our genome—linear sequence, gene transcription, and 3D structure—during postnatal cortical development. I obtained the true spectrum of somatic mutations in the normal human brain, and discovered a major transformation of both transcriptome and 3D genome in the first month of life in mice. More recently, my lab focused on the cerebellum, which exhibits a unique mode of development, maldevelopment, aging, and evolution. We discovered life-long changes in cerebellar 3D genome architecture in both human and mouse. Our work provides the first look into the “black box” of 3D genome regulation in the cerebellum, and offers tools that are widely applicable to biomedicine.