Jingyu Gavin Li

The development of single-cell assay for transposase-accessible chromatin using sequencing data (scATAC-seq) has allowed the characterization of epigenetic heterogeneity at single-cell resolution. However, the sparse and noisy nature of scATAC-seq data poses unique computational challenges. To address this, we introduce scART, a novel bioinformatics tool specifically designed for scATAC-seq data analysis. scART utilizes analytical methods highly stable for processing sparse and noisy data, such as k-nearest neighbor (KNN) imputation, Term Frequency-Inverse Document Frequency (TF-IDF) weighting scheme, and the cosine similarity metric to identify underlying cellular heterogeneity in scATAC-seq data. It accurately and robustly identifies cell identities, particularly in data with low sequencing depth, and constructs the trajectory of cellular states. As a demonstration of its utility, scART successfully reconstructed the development trajectory of the embryonic mouse forebrain and uncovered the dynamics of layer-specific neurogenesis. scART is available at GitHub.

Following gastrulation, the three primary germ layers develop into the major organs in a process known as organogenesis. Single-cell RNA sequencing has enabled the profiling of the gene expression dynamics of these cell fate decisions, yet a comprehensive map of the interplay between transcription factors and cis-regulatory elements is lacking, as are the underlying gene regulatory networks. Here we generate a multi-omics atlas of mouse early organogenesis by simultaneously profiling gene expression and chromatin accessibility from tens of thousands of single cells. We develop a computational method to leverage the multi-modal readouts to predict transcription factor binding events in cis-regulatory elements, which we then use to infer gene regulatory networks that underpin lineage commitment events. Finally, we show that these models can be used to generate in silico predictions of the effect of transcription factor perturbations. We validate this experimentally by showing that Brachyury is essential for the differentiation of neuromesodermal progenitors to somitic mesoderm fate by priming cis-regulatory elements.