3D Genome Architecture across the Life Span

Longzhi Tan, PhD

Assistant Professor

Department of Neurobiology

Stanford University

Seminar Information

Seminar Date
March 1, 2024 - 2:00 PM

The FUNG Auditorium - PFBH



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.

Speaker Bio

Originally from Wuhan, China, Tan received his S.B. in Physics (minor: Biology) from MIT in 2012, studying microbial and human evolution with Jeff Gore and Pardis Sabeti. He earned his Ph.D. in Systems Biology from Harvard in 2018, developing high-precision methods for single-cell genomics with Sunney Xie. He uncovered the 3D structure of the human genome in a single cell, revealed unique chromosome organization in the mouse eye and nose, and measured the true mutation spectrum of single neurons in the normal human brain. Tan also attended the Neurobiology course at MBL in 2014 and worked with Ibrahim Cisse at MIT in 2019. As a postdoc in Karl Deisseroth’s lab at Stanford Bioengineering (co-mentor: Howard Chang), Tan discovered major 3D genome transformation in the mouse brain after birth. Tan started his own lab at Stanford Neurobiology in Dec 2022, and discovered evolutionarily conserved 3D genome restructuring over the life spans of both humans and mice. Tan’s awards include Sanofi iAward (2024), HHMI FHS Finalist (2023), Baxter Scholarship (2023), BWF CASI (2021), ISFS (2021), Berry Fellowship (2020), Science & SciLifeLab Grand Prize (2019), HHMI ISRF (2015), and IPhO Gold Medal (2008). Outside the lab, he enjoys designing holiday cards, t-shirts, and music videos, and is a scientific illustrator.