SCSAP MSS -June 10, 2024 - Longzhi Tan, Ph.D. Stanford

TITLE: Talk title
3D Genome Architecture across the Life Span

FEATURING: Longzhi Tan, Ph.D. , Assistant Professor, Department of Neurobiology, Stanford University

ABSTRACT: 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. We developed a series of DNA sequencing-based method, including Dip-C, LiMCA, Pop-C, vDip-C, and scMicro-C, and solved the first 3D structure of the human genome in a single cell. Applying these methods to the developing mouse eye, we revealed genome-wide radial inversion of euchromatin and heterochromatin, forming a microlens to concentrate light at night. In the mouse nose, we 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, we determined the dynamics of three facets of our genome—linear sequence, gene transcription, and 3D structure—during postnatal cortical development. We 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 discovered evolutionarily conserved, lifelong changes in 3D genome architecture of cerebellar granule cells—the most abundant neuron type of the brain—in both human and mouse, forming ultra-long-range intra-chromosomal and specific inter-chromosomal contacts over the life span. This work provides a first look into the “black box” of 3D genome regulation in aging, and offers tools that are widely applicable to biomedicine.