Molecular mechanisms reconstruction from single-cell multi-omics data with HuMMuS.

MOTIVATION: The molecular identity of a cell results from a complex interplay between heterogeneous molecular layers. Recent advances in single-cell sequencing technologies have opened the possibility to measure such molecular layers of regulation. RESULTS: Here, we present HuMMuS, a new method for inferring regulatory mechanisms from single-cell multi-omics data. Differently from the state-of-the-art, HuMMuS captures cooperation between biological macromolecules and can easily include additional layers of molecular regulation. We benchmarked HuMMuS with respect to the state-of-the-art on both paired and unpaired multi-omics datasets. Our results proved the improvements provided by HuMMuS in terms of transcription factor (TF) targets, TF binding motifs and regulatory regions prediction. Finally, once applied to snmC-seq, scATAC-seq and scRNA-seq data from mouse brain cortex, HuMMuS enabled to accurately cluster scRNA profiles and to identify potential driver TFs. AVAILABILITY AND IMPLEMENTATION: HuMMuS is available at https://github.com/cantinilab/HuMMuS.

Gene regulatory network inference in the era of single-cell multi-omics.

The interplay between chromatin, transcription factors and genes generates complex regulatory circuits that can be represented as gene regulatory networks (GRNs). The study of GRNs is useful to understand how cellular identity is established, maintained and disrupted in disease. GRNs can be inferred from experimental data - historically, bulk omics data - and/or from the literature. The advent of single-cell multi-omics technologies has led to the development of novel computational methods that leverage genomic, transcriptomic and chromatin accessibility information to infer GRNs at an unprecedented resolution. Here, we review the key principles of inferring GRNs that encompass transcription factor-gene interactions from transcriptomics and chromatin accessibility data. We focus on the comparison and classification of methods that use single-cell multimodal data. We highlight challenges in GRN inference, in particular with respect to benchmarking, and potential further developments using additional data modalities.