MOTIVATION: Regulatory elements (REs), such as enhancers and promoters, are known as regulatory sequences functional in a heterogeneous regulatory network to control gene expression by recruiting transcription regulators and carrying genetic variants in a context specific way. Annotating those REs relies on costly and labor-intensive next-generation sequencing and RNA-guided editing technologies in many cellular contexts. RESULTS: We propose a systematic Gene Ontology Annotation method for Regulatory Elements (RE-GOA) by leveraging the powerful word embedding in natural language processing. We first assemble a heterogeneous network by integrating context specific regulations, protein-protein interactions and gene ontology (GO) terms. Then we perform network embedding and associate regulatory elements with GO terms by assessing their similarity in a low dimensional vector space. With three applications, we show that RE-GOA outperforms existing methods in annotating TFs' binding sites from ChIP-seq data, in functional enrichment analysis of differentially accessible peaks from ATAC-seq data, and in revealing genetic correlation among phenotypes from their GWAS summary statistics data. AVAILABILITY AND IMPLEMENTATION: The source code and the systematic RE annotation for human and mouse are available at https://github.com/AMSSwanglab/RE-GOA. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Single cell RNA-seq data offers us new resource and resolution to study cell type identity and its conversion. However, data analyses are challenging in dealing with noise, sparsity and poor annotation at single cell resolution. Detecting cell-type-indicative markers is promising to help denoising, clustering and cell type annotation. RESULTS: We developed a new method, scTIM, to reveal cell-type-indicative markers. scTIM is based on a multi-objective optimization framework to simultaneously maximize gene specificity by considering gene-cell relationship, maximize gene's ability to reconstruct cell-cell relationship and minimize gene redundancy by considering gene-gene relationship. Furthermore, consensus optimization is introduced for robust solution. Experimental results on three diverse single cell RNA-seq datasets show scTIM's advantages in identifying cell types (clustering), annotating cell types and reconstructing cell development trajectory. Applying scTIM to the large-scale mouse cell atlas data identifies critical markers for 15 tissues as 'mouse cell marker atlas', which allows us to investigate identities of different tissues and subtle cell types within a tissue. scTIM will serve as a useful method for single cell RNA-seq data mining. AVAILABILITY AND IMPLEMENTATION: scTIM is freely available at https://github.com/Frank-Orwell/scTIM. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Feature selection is the process of selecting a subset of landmark features for model construction when there are many features and a comparatively few samples. The far-reaching development technologies such as biological sequencing at single cell level make feature selection a more challenging work. The difficulty lies in four facts: those features measured are in high dimension and with noise; dropouts make the data much sparse; many features are either redundant or irrelevant; and samples are not well-labeled in the experiments. Here, we propose a new model called ELF (Extract Landmark Features) to address the above challenges. ELF aims to simultaneously maximize topology maintenance to keep the pairwise relationships among samples, minimize feature redundancy to diversify the features, and maximize feature specificity to make every selected feature more representative. This makes ELF a nonlinear combinatorial optimization. To solve this difficult problem, we propose a heuristic algorithm based on greedy strategy. We show ELF's outstanding performance on two single cell RNA-seq datasets. One is the direct reprogramming from mouse embryonic fibroblasts to induced neuron and the other is hepatoblast differentiation. ELF is able to choose only hundreds of landmark genes to maintain the cells' correlativity. Topology maintenance, redundancy removal, and specificity each plays its important role in selecting landmark features and revealing cells' biological functions. In addition, ELF can be generally applied in other scenarios. We demonstrate that ELF can reveal pivotal pixel in writing region and human face in two public image datasets. We believe that ELF is a useful tool to obtain more interpretable results by revealing key features while clustering the samples well.