PT  - JOURNAL ARTICLE
AU  - Emily Y. Su
AU  - Abby Spangler
AU  - Qin Bian
AU  - Jessica Y. Kasamoto
AU  - Patrick Cahan
TI  - Reconstruction of dynamic regulatory networks reveals signaling-induced topology changes associated with germ layer specification
AID  - 10.1101/2021.05.06.443021
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.05.06.443021
4099  - http://biorxiv.org/content/early/2021/06/10/2021.05.06.443021.short
4100  - http://biorxiv.org/content/early/2021/06/10/2021.05.06.443021.full
AB  - Elucidating regulatory relationships between transcription factors (TFs) and target genes is fundamental to understanding how cells control their identity and behavior. Computational gene regulatory network (GRN) reconstruction methods aim to map this control by inferring relationships from transcriptomic data. Unfortunately, existing methods are imprecise, may be computationally burdensome, and do not illustrate how networks transition from one topology to another. Here we present Epoch, a computational network reconstruction tool that leverages single cell transcriptomics to infer dynamic network structures. Epoch performs favorably when benchmarked using data derived from in vivo, in vitro, and in silico sources. To illustrate the usefulness of Epoch, we applied it to identify the dynamic networks underpinning directed differentiation of mouse embryonic stem cells (ESC) guided by multiple primitive streak induction treatments. Our analysis demonstrates that modulating signaling pathways drives topological network changes that shape cell fate potential. We also find that Peg3 is a central contributor to the rewiring of the pluripotency network to favor mesoderm specification. By integrating signaling pathways with GRN structures, we traced how Wnt activation and PI3K suppression govern mesoderm and endoderm specification, respectively. The methods presented here are available in the R package Epoch, and provide a foundation for future work in understanding the biological implications of dynamic regulatory structures.Competing Interest StatementThe authors have declared no competing interest.