Inference of cell type-specific gene regulatory networks on cell lineages from single cell omic datasets.

Cell type-specific gene expression patterns are outputs of transcriptional gene regulatory networks (GRNs) that connect transcription factors and signaling proteins to target genes. Single-cell technologies such as single cell RNA-sequencing (scRNA-seq) and single cell Assay for Transposase-Accessible Chromatin using sequencing (scATAC-seq), can examine cell-type specific gene regulation at unprecedented detail. However, current approaches to infer cell type-specific GRNs are limited in their ability to integrate scRNA-seq and scATAC-seq measurements and to model network dynamics on a cell lineage. To address this challenge, we have developed single-cell Multi-Task Network Inference (scMTNI), a multi-task learning framework to infer the GRN for each cell type on a lineage from scRNA-seq and scATAC-seq data. Using simulated and real datasets, we show that scMTNI is a broadly applicable framework for linear and branching lineages that accurately infers GRN dynamics and identifies key regulators of fate transitions for diverse processes such as cellular reprogramming and differentiation.

Identifying strengths and weaknesses of methods for computational network inference from single-cell RNA-seq data.

Single-cell RNA-sequencing (scRNA-seq) offers unparalleled insight into the transcriptional programs of different cellular states by measuring the transcriptome of thousands of individual cells. An emerging problem in the analysis of scRNA-seq is the inference of transcriptional gene regulatory networks and a number of methods with different learning frameworks have been developed to address this problem. Here, we present an expanded benchmarking study of eleven recent network inference methods on seven published scRNA-seq datasets in human, mouse, and yeast considering different types of gold standard networks and evaluation metrics. We evaluate methods based on their computing requirements as well as on their ability to recover the network structure. We find that, while most methods have a modest recovery of experimentally derived interactions based on global metrics such as Area Under the Precision Recall curve, methods are able to capture targets of regulators that are relevant to the system under study. Among the top performing methods that use only expression were SCENIC, PIDC, MERLIN or Correlation. Addition of prior biological knowledge and the estimation of transcription factor activities resulted in the best overall performance with the Inferelator and MERLIN methods that use prior knowledge outperforming methods that use expression alone. We found that imputation for network inference did not improve network inference accuracy and could be detrimental. Comparisons of inferred networks for comparable bulk conditions showed that the networks inferred from scRNA-seq datasets are often better or at par with the networks inferred from bulk datasets. Our analysis should be beneficial in selecting methods for network inference. At the same time, this highlights the need for improved methods and better gold standards for regulatory network inference from scRNAseq datasets.

Rapid Reconstruction of Time-varying Gene Regulatory Networks with Limited Main Memory.

Reconstruction of time-varying gene regulatory networks underlying a time-series gene expression data is a fundamental challenge in the computational systems biology. The challenge increases multi-fold if the target networks need to be constructed for hundreds to thousands of genes. There have been constant efforts to design an algorithm that can perform the reconstruction task correctly as well as can scale efficiently (with respect to both time and memory) to such a large number of genes. However, the existing algorithms either do not offer time-efficiency, or they offer it at other costs - memory-inefficiency or imposition of a constraint, known as the 'smoothly time-varying assumption'. In this article, two novel algorithms - 'an algorithm for reconstructing Time-varying Gene regulatory networks with Shortlisted candidate regulators - which is Light on memory' (TGS-Lite) and 'TGS-Lite Plus' (TGS-Lite+) - are proposed that are time-efficient, memory-efficient and do not impose the smoothly time-varying assumption. Additionally, they offer state-of-the-art reconstruction correctness as demonstrated with three benchmark datasets. Source Code: https://github.com/sap01/TGS-Lite-supplem/tree/master/sourcecode.

Rapid Reconstruction of Time-Varying Gene Regulatory Networks.

Rapid advancements in high-throughput technologies have resulted in genome-scale time series datasets. Uncovering the temporal sequence of gene regulatory events, in the form of time-varying gene regulatory networks (GRNs), demands computationally fast, accurate, and scalable algorithms. The existing algorithms can be divided into two categories: ones that are time-intensive and hence unscalable; and others that impose structural constraints to become scalable. In this paper, a novel algorithm, namely 'an algorithm for reconstructing Time-varying Gene regulatory networks with Shortlisted candidate regulators' (TGS), is proposed. TGS is time-efficient and does not impose any structural constraints. Moreover, it provides such flexibility and time-efficiency, without losing its accuracy. TGS consistently outperforms the state-of-the-art algorithms in true positive detection, on three benchmark synthetic datasets. However, TGS does not perform as well in false positive rejection. To mitigate this issue, TGS+ is proposed. TGS+ demonstrates competitive false positive rejection power, while maintaining the superior speed and true positive detection power of TGS. Nevertheless, the main memory requirements of both TGS variants grow exponentially with the number of genes, which they tackle by restricting the maximum number of regulators for each gene. Relaxing this restriction remains a challenge as the actual number of regulators is not known a priori.