Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Kamimoto, Kenji, Adil, Mohd Tayyab, Jindal, Kunal, Hoffmann, Christy M., Kong, Wenjun, Yang, Xue, Morris, Samantha A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
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
_version_ 1784874492190785536
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
work_keys_str_mv AT kamimotokenji generegulatorynetworkreconfigurationindirectlineagereprogramming
AT adilmohdtayyab generegulatorynetworkreconfigurationindirectlineagereprogramming
AT jindalkunal generegulatorynetworkreconfigurationindirectlineagereprogramming
AT hoffmannchristym generegulatorynetworkreconfigurationindirectlineagereprogramming
AT kongwenjun generegulatorynetworkreconfigurationindirectlineagereprogramming
AT yangxue generegulatorynetworkreconfigurationindirectlineagereprogramming
AT morrissamanthaa generegulatorynetworkreconfigurationindirectlineagereprogramming