Originally from Wuhan, China, Tan received his S.B. in Physics (minor: Biology) from MIT in 2012, studying 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 is an Assistant Professor of Neurobiology at Stanford, and started his lab in Dec 2022. Tan’s awards include BWF CASI (2021), ISFS (2021), Berry Fellowship (2020), Science & SciLifeLab Grand Prize (2019), HHMI ISRF (2015), and IPhO Gold Medal (2008). Outside of the lab, he enjoys designing holiday cards, t-shirts, and music videos, and is a scientific illustrator.
Honors & Awards
Innovation Award, Sanofi (2024)
Faculty Scholar, Donald E. and Delia B. Baxter Foundation (2023)
Finalist, Freeman Hrabowski Scholars Program, Howard Hughes Medical Institute (2023)
Innovators Under 35 (China Region), MIT Technology Review (2023)
Uytengsu-Hamilton 22q11 Neuropsychiatry Research Award, Stanford Maternal and Child Health Research Institute (2023)
Career Award at the Scientific Interface, Burroughs Wellcome Fund (2022 – 2027)
Bio-X Undergraduate Summer Research Program Star Mentor Award, Stanford University (2021)
Intersections Science Fellow, Yale University (2021)
Walter V. and Idun Berry Postdoctoral Fellowship, Stanford University (2020 – 2022)
School of Medicine Dean's Postdoctoral Fellowship, Stanford University (2020 – 2021)
Grand Prize, Science & SciLifeLab Prize for Young Scientists (2019)
International Student Research Fellowship, Howard Hughes Medical Institute (2015 – 2017)
Member, Sigma Pi Sigma (2012)
Member, Phi Beta Kappa (2012)
Philip Morse Memorial Award, Massachusetts Institute of Technology (2012)
Freshman Fellowship, Peking University (2008)
Gold Medal, Asian Physics Olympiad (2008)
Gold Medal and “the Absolute Winner”, International Physics Olympiad (2008)
Ph.D., Harvard University, Systems Biology (2018)
Summer course, Marine Biological Laboratory, Neurobiology (2014)
S.B., Massachusetts Institute of Technology, Physics (minor: Biology) (2012)
Freshman student, Peking University, Physics (2009)
Xiaoliang Sunney Xie, Dong Xing, Chi-Han Chang, Longzhi Tan. "United States Patent 11,530,436 Multiplex end-tagging amplification of nucleic acids", President And Fellows Of Harvard College, Dec 20, 2022
Current Research and Scholarly Interests
The Tan Lab studies the single-cell 3D genome architectural basis of neurodevelopment and aging by developing the next generation of in vivo multi-omic assays and algorithms, and applying them to the human and mouse cerebellum.
- Independent Studies (6)
Opposing, spatially-determined epigenetic forces impose restrictions on stochastic olfactory receptor choice.
Olfactory receptor (OR) choice represents an example of genetically hardwired stochasticity, where every olfactory neuron expresses one out of ~2000 OR alleles in the mouse genome in a probabilistic, yet stereotypic fashion. Here, we propose that topographic restrictions in OR expression are established in neuronal progenitors by two opposing forces: polygenic transcription and genomic silencing, both of which are influenced by dorsoventral gradients of transcription factors NFIA, B, and X. Polygenic transcription of OR genes may define spatially constrained OR repertoires, among which one OR allele is selected for singular expression later in development. Heterochromatin assembly and genomic compartmentalization of OR alleles also vary across the axes of the olfactory epithelium and may preferentially eliminate ectopically expressed ORs with more dorsal expression destinations from this 'privileged' repertoire. Our experiments identify early transcription as a potential 'epigenetic' contributor to future developmental patterning and reveal how two spatially responsive probabilistic processes may act in concert to establish deterministic, precise, and reproducible territories of stochastic gene expression.
View details for DOI 10.7554/eLife.87445
View details for PubMedID 38108811
Lifelong restructuring of 3D genome architecture in cerebellar granule cells.
Science (New York, N.Y.)
2023; 381 (6662): 1112-1119
The cerebellum contains most of the neurons in the human brain and exhibits distinctive modes of development and aging. In this work, by developing our single-cell three-dimensional (3D) genome assay-diploid chromosome conformation capture, or Dip-C-into population-scale (Pop-C) and virus-enriched (vDip-C) modes, we resolved the first 3D genome structures of single cerebellar cells, created life-spanning 3D genome atlases for both humans and mice, and jointly measured transcriptome and chromatin accessibility during development. We found that although the transcriptome and chromatin accessibility of cerebellar granule neurons mature in early postnatal life, 3D genome architecture gradually remodels throughout life, establishing ultra-long-range intrachromosomal contacts and specific interchromosomal contacts that are rarely seen in neurons. These results reveal unexpected evolutionarily conserved molecular processes that underlie distinctive features of neural development and aging across the mammalian life span.
View details for DOI 10.1126/science.adh3253
View details for PubMedID 37676945
Cardiogenic control of affective behavioural state.
Emotional states influence bodily physiology, as exemplified in the top-down process by which anxiety causes faster beating of the heart1-3. However, whether an increased heart rate might itself induce anxiety or fear responses is unclear3-8. Physiological theories of emotion, proposed over a century ago, have considered that in general, there could be an important and even dominant flow of information from the body to the brain9. Here, to formally test this idea, we developed a noninvasive optogenetic pacemaker for precise, cell-type-specific control of cardiac rhythms of up to 900beats per minute in freely moving mice, enabled by a wearable micro-LED harness and the systemic viral delivery of a potent pump-like channelrhodopsin. We found that optically evoked tachycardia potently enhanced anxiety-like behaviour, but crucially only in risky contexts, indicating that both central (brain) and peripheral (body) processes may be involved in the development of emotional states. To identify potential mechanisms, we used whole-brain activity screening and electrophysiology to find brain regions that wereactivated by imposed cardiac rhythms. We identified the posterior insular cortex as a potential mediator of bottom-up cardiac interoceptive processing, and found that optogenetic inhibition of this brain region attenuated the anxiety-like behaviour that was induced by optical cardiac pacing. Together, these findings reveal that cells of both the body and the brain must be considered together to understand the origins of emotional or affective states. More broadly, our results define a generalizable approach for noninvasive, temporally precise functional investigations of joint organism-wide interactions among targeted cells during behaviour.
View details for DOI 10.1038/s41586-023-05748-8
View details for PubMedID 36859543
Highly sensitive single-cell chromatin accessibility assay and transcriptome coassay with METATAC.
Proceedings of the National Academy of Sciences of the United States of America
2022; 119 (40): e2206450119
Recent advances in single-cell assay for transposase accessible chromatin using sequencing (scATAC-seq) and its coassays have transformed the field of single-cell epigenomics and transcriptomics. However, the low detection efficiency of current methods has limited our understanding of the true complexity of chromatin accessibility and its relationship with gene expression in single cells. Here, we report a high-sensitivity scATAC-seq method, termed multiplexed end-tagging amplification of transposase accessible chromatin (METATAC), which detects a large number of accessible sites per cell and is compatible with automation. Our high detectability and statistical framework allowed precise linking of enhancers to promoters without merging single cells. We systematically investigated allele-specific accessibility in the mouse cerebral cortex, revealing allele-specific accessibility of promotors of certain imprinted genes but biallelic accessibility of their enhancers. Finally, we combined METATAC with our high-sensitivity single-cell RNA sequencing (scRNA-seq) method, multiple annealing and looping based amplification cycles for digital transcriptomics (MALBAC-DT), to develop a joint ATAC-RNA assay, termed METATAC and MALBAC-DT coassay by sequencing (M2C-seq). M2C-seq achieved significant improvements for both ATAC and RNA compared with previous methods, with consistent performance across cell lines and early mouse embryos.
View details for DOI 10.1073/pnas.2206450119
View details for PubMedID 36161934
Every gene everywhere all at once: High-precision measurement of 3D chromosome architecture with single-cell Hi-C.
Frontiers in molecular biosciences
2022; 9: 959688
The three-dimensional (3D) structure of chromosomes influences essential biological processes such as gene expression, genome replication, and DNA damage repair and has been implicated in many developmental and degenerative diseases. In the past two centuries, two complementary genres of technology-microscopy, such as fluorescence in situ hybridization (FISH), and biochemistry, such as chromosome conformation capture (3C or Hi-C)-have revealed general principles of chromosome folding in the cell nucleus. However, the extraordinary complexity and cell-to-cell variability of the chromosome structure necessitate new tools with genome-wide coverage and single-cell precision. In the past decade, single-cell Hi-C emerges as a new approach that builds upon yet conceptually differs from bulk Hi-C assays. Instead of measuring population-averaged statistical properties of chromosome folding, single-cell Hi-C works as a proximity-based "biochemical microscope" that measures actual 3D structures of individual genomes, revealing features hidden in bulk Hi-C such as radial organization, multi-way interactions, and chromosome intermingling. Single-cell Hi-C has been used to study highly dynamic processes such as the cell cycle, cell-type-specific chromosome architecture ("structure types"), and structure-expression interplay, deepening our understanding of DNA organization and function.
View details for DOI 10.3389/fmolb.2022.959688
View details for PubMedID 36275628
Determining the 3D genome structure of a single mammalian cell with Dip-C.
2021; 2 (3): 100622
3D genome structure is highly heterogeneous among single cells and contributes to cellular functions. Our single-cell chromatin conformation capture (3C/Hi-C) technique, Dip-C, enables high-resolution (20 kb or 100nm) 3D genome structure determination from single human and mouse cells. Dip-C is robust, fast, cheap, and does not require specialized equipment. This protocol describes using human and mouse brain samples to perform Dip-C, which has also been applied to other tissue types including the human blood and mouse eye, nose, and embryo. For complete details on the use and execution of this protocol, please refer to Tan etal. (2021).
View details for DOI 10.1016/j.xpro.2021.100622
View details for PubMedID 34195675
Accurate SNV detection in single cells by transposon-based whole-genome amplification of complementary strands.
Proceedings of the National Academy of Sciences of the United States of America
2021; 118 (8)
Single-nucleotide variants (SNVs), pertinent to aging and disease, occur sporadically in the human genome, hence necessitating single-cell measurements. However, detection of single-cell SNVs suffers from false positives (FPs) due to intracellular single-stranded DNA damage and the process of whole-genome amplification (WGA). Here, we report a single-cell WGA method termed multiplexed end-tagging amplification of complementary strands (META-CS), which eliminates nearly all FPs by virtue of DNA complementarity, and achieved the highest accuracy thus far. We validated META-CS by sequencing kindred cells and human sperm, and applied it to other human tissues. Investigation of mature single human neurons revealed increasing SNVs with age and potentially unrepaired strand-specific oxidative guanine damage. We determined SNV frequencies along the genome in differentiated single human blood cells, and identified cell type-dependent mutational patterns for major types of lymphocytes.
View details for DOI 10.1073/pnas.2013106118
View details for PubMedID 33593904
Changes in genome architecture and transcriptional dynamics progress independently of sensory experience during post-natal brain development.
Both transcription and three-dimensional (3D) architecture of the mammalian genome play critical roles in neurodevelopment and its disorders. However, 3D genome structures of single brain cells have not been solved; little is known about the dynamics of single-cell transcriptome and 3D genome after birth. Here, we generated a transcriptome (3,517 cells) and 3D genome (3,646 cells) atlas of the developing mouse cortex and hippocampus by using our high-resolution multiple annealing and looping-based amplification cycles for digital transcriptomics (MALBAC-DT) and diploid chromatin conformation capture (Dip-C) methods and developing multi-omic analysis pipelines. In adults, 3D genome "structure types" delineate all major cell types, with high correlation between chromatin A/B compartments and gene expression. During development, both transcriptome and 3D genome are extensively transformed in the first post-natal month. In neurons, 3D genome is rewired across scales, correlated with gene expression modules, and independent of sensory experience. Finally, we examine allele-specific structure of imprinted genes, revealing local and chromosome (chr)-wide differences. These findings uncover an unknown dimension of neurodevelopment.
View details for DOI 10.1016/j.cell.2020.12.032
View details for PubMedID 33484631
- Three-dimensional genome structure of a single cell. Science (New York, N.Y.) 2019; 366 (6468): 964–65
Three-dimensional genome structures of single sensory neurons in mouse visual and olfactory systems
NATURE STRUCTURAL & MOLECULAR BIOLOGY
2019; 26 (4): 297-+
Sensory neurons in the mouse eye and nose have unusual chromatin organization. Here we report their three-dimensional (3D) genome structure at 20-kilobase (kb) resolution, achieved by applying our recently developed diploid chromatin conformation capture (Dip-C) method to 409 single cells from the retina and the main olfactory epithelium of adult and newborn mice. The 3D genome of rod photoreceptors exhibited inverted radial distribution of euchromatin and heterochromatin compared with that of other cell types, whose nuclear periphery is mainly heterochromatin. Such genome-wide inversion is not observed in olfactory sensory neurons (OSNs). However, OSNs exhibited an interior bias for olfactory receptor (OR) genes and enhancers, in clear contrast to non-neuronal cells. Each OSN harbored multiple aggregates of OR genes and enhancers from different chromosomes. We also observed structural heterogeneity of the protocadherin gene cluster. This type of genome organization may provide the structural basis of the 'one-neuron, one-receptor' rule of olfaction.
View details for DOI 10.1038/s41594-019-0205-2
View details for Web of Science ID 000463168900011
View details for PubMedID 30936528
Three-dimensional genome structures of single diploid human cells
2018; 361 (6405): 924–28
Three-dimensional genome structures play a key role in gene regulation and cell functions. Characterization of genome structures necessitates single-cell measurements. This has been achieved for haploid cells but has remained a challenge for diploid cells. We developed a single-cell chromatin conformation capture method, termed Dip-C, that combines a transposon-based whole-genome amplification method to detect many chromatin contacts, called META (multiplex end-tagging amplification), and an algorithm to impute the two chromosome haplotypes linked by each contact. We reconstructed the genome structures of single diploid human cells from a lymphoblastoid cell line and from primary blood cells with high spatial resolution, locating specific single-nucleotide and copy number variations in the nucleus. The two alleles of imprinted loci and the two X chromosomes were structurally different. Cells of different types displayed statistically distinct genome structures. Such structural cell typing is crucial for understanding cell functions.
View details for DOI 10.1126/science.aat5641
View details for Web of Science ID 000443547000040
View details for PubMedID 30166492
View details for PubMedCentralID PMC6360088
A Near-Complete Spatial Map of Olfactory Receptors in the Mouse Main Olfactory Epithelium
2018; 43 (6): 427–32
Different regions of the mammalian nose smell different odors. In the mouse olfactory system, spatially regulated expression of >1000 olfactory receptors (ORs) along the dorsomedial-ventrolateral (DV) axis forms a topological map in the main olfactory epithelium (MOE). However, the locations of most ORs along the DV axis are currently unknown. By sequencing mRNA of 12 isolated MOE pieces, we mapped out the DV locations-as quantified by "zone indices" on a scale of 1-5-of 1033 OR genes with an estimated error of 0.3 zone indices. Our map covered 81% of all intact OR genes and 99.4% of the total OR mRNA abundance. Spatial regulation tended to vary gradually along chromosomes. We further identified putative non-OR genes that may exhibit spatial expression along the DV axis.
View details for DOI 10.1093/chemse/bjy030
View details for Web of Science ID 000438293600005
View details for PubMedID 29796642
View details for PubMedCentralID PMC6454507
Single-cell whole-genome analyses by Linear Amplification via Transposon Insertion (LIANTI)
2017; 356 (6334): 189–94
Single-cell genomics is important for biology and medicine. However, current whole-genome amplification (WGA) methods are limited by low accuracy of copy-number variation (CNV) detection and low amplification fidelity. Here we report an improved single-cell WGA method, Linear Amplification via Transposon Insertion (LIANTI), which outperforms existing methods, enabling micro-CNV detection with kilobase resolution. This allowed direct observation of stochastic firing of DNA replication origins, which differs from cell to cell. We also show that the predominant cytosine-to-thymine mutations observed in single-cell genomics often arise from the artifact of cytosine deamination upon cell lysis. However, identifying single-nucleotide variations (SNVs) can be accomplished by sequencing kindred cells. We determined the spectrum of SNVs in a single human cell after ultraviolet radiation, revealing their nonrandom genome-wide distribution.
View details for DOI 10.1126/science.aak9787
View details for Web of Science ID 000399013800037
View details for PubMedID 28408603
View details for PubMedCentralID PMC5538131
Olfactory sensory neurons transiently express multiple olfactory receptors during development
MOLECULAR SYSTEMS BIOLOGY
2015; 11 (12): 844
In mammals, each olfactory sensory neuron randomly expresses one, and only one, olfactory receptor (OR)--a phenomenon called the "one-neuron-one-receptor" rule. Although extensively studied, this rule was never proven for all ~1,000 OR genes in one cell at once, and little is known about its dynamics. Here, we directly tested this rule by single-cell transcriptomic sequencing of 178 cells from the main olfactory epithelium of adult and newborn mice. To our surprise, a subset of cells expressed multiple ORs. Most of these cells were developmentally immature. Our results illustrated how the "one-neuron-one-receptor" rule may have been established: At first, a single neuron temporarily expressed multiple ORs--seemingly violating the rule--and then all but one OR were eliminated. This work provided experimental evidence that epigenetic regulation in the olfactory system selects a single OR by suppressing a few transiently expressed ORs in a single cell during development.
View details for DOI 10.15252/msb.20156639
View details for Web of Science ID 000368086600009
View details for PubMedID 26646940
View details for PubMedCentralID PMC4704490
Single Cell Transcriptome Amplification with MALBAC
2015; 10 (3): e0120889
Recently, Multiple Annealing and Looping-Based Amplification Cycles (MALBAC) has been developed for whole genome amplification of an individual cell, relying on quasilinear instead of exponential amplification to achieve high coverage. Here we adapt MALBAC for single-cell transcriptome amplification, which gives consistently high detection efficiency, accuracy and reproducibility. With this newly developed technique, we successfully amplified and sequenced single cells from 3 germ layers from mouse embryos in the early gastrulation stage, and examined the epithelial-mesenchymal transition (EMT) program among cells in the mesoderm layer on a single-cell level.
View details for DOI 10.1371/journal.pone.0120889
View details for Web of Science ID 000352134700079
View details for PubMedID 25822772
View details for PubMedCentralID PMC4378937
Rare event of histone demethylation can initiate singular gene expression of olfactory receptors
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2013; 110 (52): 21148–52
Mammals sense odors through the gene family of olfactory receptors (ORs). Despite the enormous number of OR genes (∼1,400 in mouse), each olfactory sensory neuron expresses one, and only one, of them. In neurobiology, it remains a long-standing mystery how this singularity can be achieved despite intrinsic stochasticity of gene expression. Recent experiments showed an epigenetic mechanism for maintaining singular OR expression: Once any ORs are activated, their expression inhibits further OR activation by down-regulating a histone demethylase Lsd1 (also known as Aof2 or Kdm1a), an enzyme required for the removal of the repressive histone marker H3K9me3 on OR genes. However, it remains unclear at a quantitative level how singularity can be initiated in the first place. In particular, does a simple activation/feedback scheme suffice to generate singularity? Here we show theoretically that rare events of histone demethylation can indeed produce robust singularity by separating two timescales: slow OR activation by stepwise H3K9me3 demethylation, and fast feedback to turn off Lsd1. Given a typical 1-h response of transcriptional feedback, to achieve the observed extent of singularity (only 2% of neurons express more than one ORs), we predict that OR activation must be as slow as 5–10 d-a timescale compatible with experiments. Our model further suggests H3K9me3-to-H3K9me2 demethylation as an additional rate-limiting step responsible for OR singularity. Our conclusions may be generally applicable to other systems where monoallelic expression is desired, and provide guidelines for the design of a synthetic system of singular expression.
View details for DOI 10.1073/pnas.1321511111
View details for Web of Science ID 000328858800069
View details for PubMedID 24344257
View details for PubMedCentralID PMC3876194
Modeling Recent Human Evolution in Mice by Expression of a Selected EDAR Variant
2013; 152 (4): 691–702
An adaptive variant of the human Ectodysplasin receptor, EDARV370A, is one of the strongest candidates of recent positive selection from genome-wide scans. We have modeled EDAR370A in mice and characterized its phenotype and evolutionary origins in humans. Our computational analysis suggests the allele arose in central China approximately 30,000 years ago. Although EDAR370A has been associated with increased scalp hair thickness and changed tooth morphology in humans, its direct biological significance and potential adaptive role remain unclear. We generated a knockin mouse model and find that, as in humans, hair thickness is increased in EDAR370A mice. We identify new biological targets affected by the mutation, including mammary and eccrine glands. Building on these results, we find that EDAR370A is associated with an increased number of active eccrine glands in the Han Chinese. This interdisciplinary approach yields unique insight into the generation of adaptive variation among modern humans.
View details for DOI 10.1016/j.cell.2013.01.016
View details for Web of Science ID 000314945600006
View details for PubMedID 23415220
View details for PubMedCentralID PMC3575602
SLOWLY SWITCHING BETWEEN ENVIRONMENTS FACILITATES REVERSE EVOLUTION IN SMALL POPULATIONS
2012; 66 (10): 3144–54
Natural populations must constantly adapt to ever-changing environmental conditions. A particularly interesting question is whether such adaptations can be reversed by returning the population to an ancestral environment. Such evolutionary reversals have been observed in both natural and laboratory populations. However, the factors that determine the reversibility of evolution are still under debate. The time scales of environmental change vary over a wide range, but little is known about how the rate of environmental change influences the reversibility of evolution. Here, we demonstrate computationally that slowly switching between environments increases the reversibility of evolution for small populations that are subject to only modest clonal interference. For small populations, slow switching reduces the mean number of mutations acquired in a new environment and also increases the probability of reverse evolution at each of these "genetic distances." As the population size increases, slow switching no longer reduces the genetic distance, thus decreasing the evolutionary reversibility. We confirm this effect using both a phenomenological model of clonal interference and also a Wright-Fisher stochastic simulation that incorporates genetic diversity. Our results suggest that the rate of environmental change is a key determinant of the reversibility of evolution, and provides testable hypotheses for experimental evolution.
View details for DOI 10.1111/j.1558-5646.2012.01680.x
View details for Web of Science ID 000309393000012
View details for PubMedID 23025604
Hidden Randomness between Fitness Landscapes Limits Reverse Evolution
PHYSICAL REVIEW LETTERS
2011; 106 (19): 198102
In biological evolution, adaptations to one environment can in some cases reverse adaptations to another environment. To study this "reverse evolution" on a genotypic level, we measured the fitness of E. coli strains with each possible combination of five mutations in an antibiotic-resistance gene in two distinct antibiotic environments. While adaptations to one environment generally lower fitness in the other, we find that reverse evolution is rarely possible and falls as the complexity of adaptations increases, suggesting a probabilistic, molecular form of Dollo's law.
View details for DOI 10.1103/PhysRevLett.106.198102
View details for Web of Science ID 000290474100022
View details for PubMedID 21668204