RT Journal Article
SR Electronic
T1 Gene Regulatory Network Reconfiguration in Direct Lineage Reprogramming
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.07.01.497374
DO 10.1101/2022.07.01.497374
A1 Kenji Kamimoto
A1 Mohd Tayyab Adil
A1 Kunal Jindal
A1 Christy M. Hoffmann
A1 Wenjun Kong
A1 Xue Yang
A1 Samantha A. Morris
YR 2022
UL http://biorxiv.org/content/early/2022/07/03/2022.07.01.497374.abstract
AB In direct lineage reprogramming, transcription factor (TF) overexpression reconfigures Gene Regulatory Networks (GRNs) to convert cell identities between fully differentiated cell types. We previously developed CellOracle, a computational pipeline that integrates single-cell transcriptome and epigenome profiles to infer GRNs. CellOracle leverages these inferred GRNs to simulate gene expression changes in response to TF perturbation, enabling network re-configuration during reprogramming to be interrogated in silico. Here, we integrate CellOracle analysis with lineage tracing of fibroblast to induced endoderm progenitor (iEP) conversion, a prototypical direct lineage reprogramming paradigm. By linking early network state to reprogramming success or failure, we reveal distinct network configurations underlying different reprogramming outcomes. Using these network analyses and in silico simulation of TF perturbation, we identify new factors to coax cells into successfully converting cell identity, uncovering a central role for the AP-1 subunit Fos with the Hippo signaling effector, Yap1. Together, these results demonstrate the efficacy of CellOracle to infer and interpret cell-type-specific GRN configurations at high resolution, providing new mechanistic insights into the regulation and reprogramming of cell identity.Competing Interest StatementSamantha Morris is co-founder of CapyBio LLC.