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Gene Regulatory Network Reconfiguration in Direct Lineage Reprogramming

Gene Regulatory Network Reconfiguration in Direct Lineage Reprogramming

https://devfeature-collection.sl.nsw.gov.au/record/TN_cdi_proquest_journals_2683836442

Gene Regulatory Network Reconfiguration in Direct Lineage Reprogramming

About this item

Full title

Gene Regulatory Network Reconfiguration in Direct Lineage Reprogramming

Publisher

Cold Spring Harbor: Cold Spring Harbor Laboratory Press

Journal title

bioRxiv, 2022-07

Language

English

Formats

Publication information

Publisher

Cold Spring Harbor: Cold Spring Harbor Laboratory Press

More information

Scope and Contents

Contents

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 Statement Samantha Morris is co-founder of CapyBio LLC. Footnotes * https://github.com/morris-lab/CellOracle * https://github.com/morris-lab/Capybara...

Alternative Titles

Full title

Gene Regulatory Network Reconfiguration in Direct Lineage Reprogramming

Identifiers

Primary Identifiers

Record Identifier

TN_cdi_proquest_journals_2683836442

Permalink

https://devfeature-collection.sl.nsw.gov.au/record/TN_cdi_proquest_journals_2683836442

Other Identifiers

E-ISSN

2692-8205

DOI

10.1101/2022.07.01.497374