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Gene regulatory network reconfiguration in direct lineage reprogramming
In direct lineage conversion, transcription factor (TF) overexpression reconfigures gene regulatory networks (GRNs) to reprogram cell identity. We previously developed CellOracle, a computational method to infer GRNs from single-cell transcriptome and epigenome data. Using inferred GRNs, CellOracle...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9860067/ https://www.ncbi.nlm.nih.gov/pubmed/36584685 http://dx.doi.org/10.1016/j.stemcr.2022.11.010 |
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author | Kamimoto, Kenji Adil, Mohd Tayyab Jindal, Kunal Hoffmann, Christy M. Kong, Wenjun Yang, Xue Morris, Samantha A. |
author_facet | Kamimoto, Kenji Adil, Mohd Tayyab Jindal, Kunal Hoffmann, Christy M. Kong, Wenjun Yang, Xue Morris, Samantha A. |
author_sort | Kamimoto, Kenji |
collection | PubMed |
description | In direct lineage conversion, transcription factor (TF) overexpression reconfigures gene regulatory networks (GRNs) to reprogram cell identity. We previously developed CellOracle, a computational method to infer GRNs from single-cell transcriptome and epigenome data. Using inferred GRNs, CellOracle simulates gene expression changes in response to TF perturbation, enabling in silico interrogation of network reconfiguration. Here, we combine CellOracle analysis with lineage tracing of fibroblast to induced endoderm progenitor (iEP) conversion, a prototypical direct reprogramming paradigm. By linking early network state to reprogramming outcome, we reveal distinct network configurations underlying successful and failed fate conversion. Via in silico simulation of TF perturbation, we identify new factors to coax cells into successfully converting their 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, providing new mechanistic insights into lineage reprogramming. |
format | Online Article Text |
id | pubmed-9860067 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-98600672023-01-22 Gene regulatory network reconfiguration in direct lineage reprogramming Kamimoto, Kenji Adil, Mohd Tayyab Jindal, Kunal Hoffmann, Christy M. Kong, Wenjun Yang, Xue Morris, Samantha A. Stem Cell Reports Article In direct lineage conversion, transcription factor (TF) overexpression reconfigures gene regulatory networks (GRNs) to reprogram cell identity. We previously developed CellOracle, a computational method to infer GRNs from single-cell transcriptome and epigenome data. Using inferred GRNs, CellOracle simulates gene expression changes in response to TF perturbation, enabling in silico interrogation of network reconfiguration. Here, we combine CellOracle analysis with lineage tracing of fibroblast to induced endoderm progenitor (iEP) conversion, a prototypical direct reprogramming paradigm. By linking early network state to reprogramming outcome, we reveal distinct network configurations underlying successful and failed fate conversion. Via in silico simulation of TF perturbation, we identify new factors to coax cells into successfully converting their 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, providing new mechanistic insights into lineage reprogramming. Elsevier 2022-12-29 /pmc/articles/PMC9860067/ /pubmed/36584685 http://dx.doi.org/10.1016/j.stemcr.2022.11.010 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Kamimoto, Kenji Adil, Mohd Tayyab Jindal, Kunal Hoffmann, Christy M. Kong, Wenjun Yang, Xue Morris, Samantha A. Gene regulatory network reconfiguration in direct lineage reprogramming |
title | Gene regulatory network reconfiguration in direct lineage reprogramming |
title_full | Gene regulatory network reconfiguration in direct lineage reprogramming |
title_fullStr | Gene regulatory network reconfiguration in direct lineage reprogramming |
title_full_unstemmed | Gene regulatory network reconfiguration in direct lineage reprogramming |
title_short | Gene regulatory network reconfiguration in direct lineage reprogramming |
title_sort | gene regulatory network reconfiguration in direct lineage reprogramming |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9860067/ https://www.ncbi.nlm.nih.gov/pubmed/36584685 http://dx.doi.org/10.1016/j.stemcr.2022.11.010 |
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