Inferring gene regulatory networks from time-series scRNA-seq data via GRANGER causal recurrent autoencoders

Liang Chen; Madison Dautle; Ruoying Gao; Shaoqiang Zhang; Yong Chen

doi:10.1093/bib/bbaf089

Inferring gene regulatory networks from time-series scRNA-seq data via GRANGER causal recurrent autoencoders

Liang Chen, Madison Dautle, Ruoying Gao, Shaoqiang Zhang, Yong Chen

Biological Sciences

Rowan University

Research output: Contribution to journal › Article › peer-review

Abstract

The development of single-cell RNA sequencing (scRNA-seq) technology provides valuable data resources for inferring gene regulatory networks (GRNs), enabling deeper insights into cellular mechanisms and diseases. While many methods exist for inferring GRNs from static scRNA-seq data, current approaches face challenges in accurately handling time-series scRNA-seq data due to high noise levels and data sparsity. The temporal dimension introduces additional complexity by requiring models to capture dynamic changes, increasing sensitivity to noise, and exacerbating data sparsity across time points. In this study, we introduce GRANGER, an unsupervised deep learning-based method that integrates multiple advanced techniques, including a recurrent variational autoencoder, GRANGER causality, sparsity-inducing penalties, and negative binomial (NB)-based loss functions, to infer GRNs. GRANGER was evaluated using multiple popular benchmarking datasets, where it demonstrated superior performance compared to eight well-known GRN inference methods. The integration of a NB-based loss function and sparsity-inducing penalties in GRANGER significantly enhanced its capacity to address dropout noise and sparsity in scRNA-seq data. Additionally, GRANGER exhibited robustness against high levels of dropout noise. We applied GRANGER to scRNA-seq data from the whole mouse brain obtained through the BRAIN Initiative project and identified GRNs for five transcription regulators: E2f7, Gbx1, Sox10, Prox1, and Onecut2, which play crucial roles in diverse brain cell types. The inferred GRNs not only recalled many known regulatory relationships but also revealed sets of novel regulatory interactions with functional potential. These findings demonstrate that GRANGER is a highly effective tool for real-world applications in discovering novel gene regulatory relationships.

Original language	American English
Article number	bbaf089
Journal	Briefings in bioinformatics
Volume	26
Issue number	2
DOIs	https://doi.org/10.1093/bib/bbaf089
State	Published - Mar 1 2025

ASJC Scopus subject areas

Information Systems
Molecular Biology

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10.1093/bib/bbaf089

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title = "Inferring gene regulatory networks from time-series scRNA-seq data via GRANGER causal recurrent autoencoders",

abstract = "The development of single-cell RNA sequencing (scRNA-seq) technology provides valuable data resources for inferring gene regulatory networks (GRNs), enabling deeper insights into cellular mechanisms and diseases. While many methods exist for inferring GRNs from static scRNA-seq data, current approaches face challenges in accurately handling time-series scRNA-seq data due to high noise levels and data sparsity. The temporal dimension introduces additional complexity by requiring models to capture dynamic changes, increasing sensitivity to noise, and exacerbating data sparsity across time points. In this study, we introduce GRANGER, an unsupervised deep learning-based method that integrates multiple advanced techniques, including a recurrent variational autoencoder, GRANGER causality, sparsity-inducing penalties, and negative binomial (NB)-based loss functions, to infer GRNs. GRANGER was evaluated using multiple popular benchmarking datasets, where it demonstrated superior performance compared to eight well-known GRN inference methods. The integration of a NB-based loss function and sparsity-inducing penalties in GRANGER significantly enhanced its capacity to address dropout noise and sparsity in scRNA-seq data. Additionally, GRANGER exhibited robustness against high levels of dropout noise. We applied GRANGER to scRNA-seq data from the whole mouse brain obtained through the BRAIN Initiative project and identified GRNs for five transcription regulators: E2f7, Gbx1, Sox10, Prox1, and Onecut2, which play crucial roles in diverse brain cell types. The inferred GRNs not only recalled many known regulatory relationships but also revealed sets of novel regulatory interactions with functional potential. These findings demonstrate that GRANGER is a highly effective tool for real-world applications in discovering novel gene regulatory relationships.",

author = "Liang Chen and Madison Dautle and Ruoying Gao and Shaoqiang Zhang and Yong Chen",

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N2 - The development of single-cell RNA sequencing (scRNA-seq) technology provides valuable data resources for inferring gene regulatory networks (GRNs), enabling deeper insights into cellular mechanisms and diseases. While many methods exist for inferring GRNs from static scRNA-seq data, current approaches face challenges in accurately handling time-series scRNA-seq data due to high noise levels and data sparsity. The temporal dimension introduces additional complexity by requiring models to capture dynamic changes, increasing sensitivity to noise, and exacerbating data sparsity across time points. In this study, we introduce GRANGER, an unsupervised deep learning-based method that integrates multiple advanced techniques, including a recurrent variational autoencoder, GRANGER causality, sparsity-inducing penalties, and negative binomial (NB)-based loss functions, to infer GRNs. GRANGER was evaluated using multiple popular benchmarking datasets, where it demonstrated superior performance compared to eight well-known GRN inference methods. The integration of a NB-based loss function and sparsity-inducing penalties in GRANGER significantly enhanced its capacity to address dropout noise and sparsity in scRNA-seq data. Additionally, GRANGER exhibited robustness against high levels of dropout noise. We applied GRANGER to scRNA-seq data from the whole mouse brain obtained through the BRAIN Initiative project and identified GRNs for five transcription regulators: E2f7, Gbx1, Sox10, Prox1, and Onecut2, which play crucial roles in diverse brain cell types. The inferred GRNs not only recalled many known regulatory relationships but also revealed sets of novel regulatory interactions with functional potential. These findings demonstrate that GRANGER is a highly effective tool for real-world applications in discovering novel gene regulatory relationships.

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Inferring gene regulatory networks from time-series scRNA-seq data via GRANGER causal recurrent autoencoders

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