Biology subjects

Sun, E. D.

Publications and source records attributed to Sun, E. D..

6 recordsLinked to original sources

bioRxiv2025

SpatialProp: tissue perturbation modeling with spatially resolved single-cell transcriptomics

Perturbational studies are the gold standard for identifying causal relationships between components of biological systems. Recent technological advances, including Perturb-seq and related assays, have enabled high-throughput screening of genetic perturbation effects on single cells. Several machine learning tools have also been developed to infer the effect of single-cell perturbations. However, both approaches are generally limited to dissociated cells, and the effect of genetic perturbations on neighboring cells within intact tissue has not yet been explored. Here we introduce a computational framework using graph neural networks for predicting the effect of multi-gene, multi-cell type perturbations on cells in whole tissue sections. We leverage the natural heterogeneity in tissue microenvironments across spatially resolved single-cell transcriptomics datasets to train SpatialProp (Spatial Propagation of Single-cell Perturbations). We show that SpatialProp can predict gene expression from the tissue microenvironment and map fine-grained steering of tissue microenvironments to new target states. To assess for causal enrichment in spatial perturbation predictions, we propose CausalInteractionBench, a bidirectional benchmarking approach using curated cell-cell interactions. Under this benchmark, we evaluate the causal utility of SpatialProp in predicting the spatial effects of different perturbations. SpatialProp provides a framework towards rapid hypothesis generation and in silico perturbation experiments, particularly in the study of spatially patterned tissue biology.

bioinformatics↗

bioRxiv2024

Spatiotemporal transcriptomic profiling and modeling of mouse brain at single-cell resolution reveals cell proximity effects of aging and rejuvenation

Old age is associated with a decline in cognitive function and an increase in neurodegenerative disease risk1. Brain aging is complex and accompanied by many cellular changes2-20. However, the influence that aged cells have on neighboring cells and how this contributes to tissue decline is unknown. More generally, the tools to systematically address this question in aging tissues have not yet been developed. Here, we generate spatiotemporal data at single-cell resolution for the mouse brain across lifespan, and we develop the first machine learning models based on spatial transcriptomics ( spatial aging clocks) to reveal cell proximity effects during brain aging and rejuvenation. We collect a single-cell spatial transcriptomics brain atlas of 4.2 million cells from 20 distinct ages and across two rejuvenating interventions--exercise and partial reprogramming. We identify spatial and cell type-specific transcriptomic fingerprints of aging, rejuvenation, and disease, including for rare cell types. Using spatial aging clocks and deep learning models, we find that T cells, which infiltrate the brain with age, have a striking pro-aging proximity effect on neighboring cells. Surprisingly, neural stem cells have a strong pro-rejuvenating effect on neighboring cells. By developing computational tools to identify mediators of these proximity effects, we find that pro-aging T cells trigger a local inflammatory response likely via interferon-{gamma} whereas pro-rejuvenating neural stem cells impact the metabolism of neighboring cells possibly via growth factors (e.g. vascular endothelial growth factor) and extracellular vesicles, and we experimentally validate some of these predictions. These results suggest that rare cells can have a drastic influence on their neighbors and could be targeted to counter tissue aging. We anticipate that these spatial aging clocks will not only allow scalable assessment of the efficacy of interventions for aging and disease but also represent a new tool for studying cell-cell interactions in many spatial contexts.

neuroscience↗

bioRxiv2024

SPRITE: improving spatial gene expression imputation with gene and cell networks

Spatially resolved single-cell transcriptomics have provided unprecedented insights into gene expression in situ, particularly in the context of cell interactions or organization of tissues. However, current technologies for profiling spatial gene expression at single-cell resolution are generally limited to the measurement of a small number of genes. To address this limitation, several algorithms have been developed to impute or predict the expression of additional genes that were not present in the measured gene panel. Current algorithms do not leverage the rich spatial and gene relational information in spatial transcriptomics. To improve spatial gene expression predictions, we introduce SPRITE (Spatial Propagation and Reinforcement of Imputed Transcript Expression) as a meta-algorithm that processes predictions obtained from existing methods by propagating information across gene correlation networks and spatial neighborhood graphs. SPRITE improves spatial gene expression predictions across multiple spatial transcriptomics datasets. Furthermore, SPRITE predicted spatial gene expression leads to improved clustering, visualization, and classification of cells. SPRITE is available as a software package and can be used in spatial transcriptomics data analysis to improve inferences based on predicted gene expression.

bioinformatics↗

bioRxiv2023

Is your data alignable? Principled and interpretable alignability testing and integration of single-cell data

Single-cell data integration can provide a comprehensive molecular view of cells, and many algorithms have been developed to remove unwanted technical or biological variations and integrate heterogeneous single-cell datasets. Despite their wide usage, existing methods suffer from several fundamental limitations. In particular, we lack a rigorous statistical test for whether two high-dimensional single-cell datasets are alignable (and therefore should even be aligned). Moreover, popular methods can substantially distort the data during alignment, making the aligned data and downstream analysis difficult to interpret. To overcome these limitations, we present a spectral manifold alignment and inference (SMAI) framework, which enables principled and interpretable alignability testing and structure-preserving integration of single-cell data. SMAI provides a statistical test to robustly determine the alignability between datasets to avoid misleading inference, and is justified by high-dimensional statistical theory. On a diverse range of real and simulated benchmark datasets, it outperforms commonly used alignment methods. Moreover, we show that SMAI improves various downstream analyses such as identification of differentially expressed genes and imputation of single-cell spatial transcriptomics, providing further biological insights. SMAIs interpretability also enables quantification and a deeper understanding of the sources of technical confounders in single-cell data.

bioinformatics↗

bioRxiv2022

A Spectral Method for Assessing and Combining Multiple Data Visualizations

Dimension reduction and data visualization aim to project a high-dimensional dataset to a low-dimensional space while capturing the intrinsic structures in the data. It is an indispensable part of modern data science, and many dimensional reduction and visualization algorithms have been developed. However, different algorithms have their own strengths and weaknesses, making it critically important to evaluate their relative performance for a given dataset, and to leverage and combine their individual strengths. In this paper, we propose an efficient spectral method for assessing and combining multiple visualizations of a given dataset produced by diverse algorithms. The proposed method provides a quantitative measure - the visualization eigenscore - of the relative performance of the visualizations for preserving the structure around each data point. Then it leverages the eigenscores to obtain a consensus visualization, which has much improved quality over the individual visualizations in capturing the underlying true data structure. Our approach is flexible and works as a wrapper around any visualizations. We analyze multiple simulated and real-world datasets from diverse applications to demonstrate the effectiveness of the eigenscores for evaluating visualizations and the superiority of the proposed consensus visualization. Furthermore, we establish rigorous theoretical justification of our method based on a general statistical framework, yielding fundamental principles behind the empirical success of consensus visualization along with practical guidance.

bioinformatics↗

bioRxiv2022

Dynamic visualization of high-dimensional data

Dimensionality reduction (DR) is commonly used to project highdimensional data into lower dimensions for visualization, which could then generate new insights and hypotheses. However, DR algorithms necessarily introduce distortions in the visualization and cannot faithfully represent all relations in the data. As such, there is a need for methods to assess the reliability of DR visualizations. Here we present DynamicViz, a framework for generating dynamic visualizations that capture the sensitivity of DR visualizations to perturbations in the data. DynamicVic can be applied to all commonly used DR methods. We show the utility of dynamic visualizations in diagnosing common interpretative pitfalls of static visualizations and extending existing single-cell analyses. We introduce the variance score to quantify the dynamic variability of observations in these visualizations. The variance score characterizes natural variability in the data and can be used to optimize DR algorithm implementations. We have made DynamicViz freely available to assist with the evaluation of DR visualizations.

bioinformatics↗