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| Status |
Public on Dec 20, 2022 |
| Title |
Gene Regulatory Network Reconfiguration in Direct Lineage Reprogramming |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
For lineage tracing, scRNA-seq was performed for CellTagged in vitro reprogramming MEFs at multiple time points to allow longitudinal lineage tracing. For Fos-Yap1 experiments, scRNA-seq was performed for reprogramming iEPs on Day 20
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| Contributor(s) |
Kamimoto K, Adil MT, Jindal K, Hoffmann C, Kong W, Yang X, Morris S |
| Citation(s) |
36584685 |
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| Submission date |
Nov 09, 2022 |
| Last update date |
Feb 07, 2023 |
| Contact name |
Samantha Morris |
| E-mail(s) |
s.morris@wustl.edu
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| Organization name |
Washington University School of Medicine
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| Street address |
660 S Euclid Ave
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| City |
Saint Louis |
| State/province |
Missouri |
| ZIP/Postal code |
63110 |
| Country |
USA |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (7)
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| Relations |
| BioProject |
PRJNA899923 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE217675_RAW.tar |
190.5 Mb |
(http)(custom) |
TAR (of H5) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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