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Cited by 39Pluripotent Stem Cells ResearchGene Regulatory Network AnalysisPeroxisome Proliferator-Activated Receptors

A transient disruption of fibroblastic transcriptional regulatory network facilitates trans-differentiation

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Tomaru, Yasuhiro, Hasegawa, Ryota, Suzuki, Takahiro, Sato, Taiji, Kubosaki, Atsutaka, Suzuki, Masanori, Kawaji, Hideya, Forrest, Alistair R.R. +4 more·2014·Nucleic Acids Research
DOI 10.1093/nar/gku567PMC PMC4132712
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Abstract

Transcriptional Regulatory Networks (TRNs) coordinate multiple transcription factors (TFs) in concert to maintain tissue homeostasis and cellular function. The re-establishment of target cell TRNs has been previously implicated in direct trans-differentiation studies where the newly introduced TFs switch on a set of key regulatory factors to induce de novo expression and function. However, the extent to which TRNs in starting cell types, such as dermal fibroblasts, protect cells from undergoing cellular reprogramming remains largely unexplored. In order to identify TFs specific to maintaining the fibroblast state, we performed systematic knockdown of 18 fibroblast-enriched TFs and analyzed differential mRNA expression against the same 18 genes, building a Matrix-RNAi. The resulting expression matrix revealed seven highly interconnected TFs. Interestingly, suppressing four out of seven TFs generated lipid droplets and induced PPARG and CEBPA expression in the presence of adipocyte-inducing medium only, while negative control knockdown cells maintained fibroblastic character in the same induction regime. Global gene expression analyses further revealed that the knockdown-induced adipocytes expressed genes associated with lipid metabolism and significantly suppressed fibroblast genes. Overall, this study reveals the critical role of the TRN in protecting cells against aberrant reprogramming, and demonstrates the vulnerability of donor cell's TRNs, offering a novel strategy to induce transgene-free trans-differentiations.

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  • PRRX1 and TWIST1 were identified as key members of fibroblast transcriptional regulatory networks and are involved in a positive feedback loop that leads to fibroblast activation.

    “They were both identified as key members of fibroblast transcriptional regulatory networks and involved in a positive feedback loop that leads to fibroblast activation16,17.”

    From Integrative genomic analyses identify candidate causal genes for calcific aortic valve stenosis involving tissue-specific regulation (2024) · cites this paper as [16]

    In Results, 'Building a fibroblastic TRN model by Matrix-RNAi' (page unavailable), PRRX1 is identified as an influential network member, but the interconnected TWIST factor is TWIST2, not TWIST1. Table 1 in Results lists TWIST1 among 18 fibroblast-enriched factors, but the paper does not establish a PRRX1–TWIST1 positive feedback loop leading to fibroblast activation. (LLM, conf=0.88)

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Cited by

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Authors
Tomaru, Y., Hasegawa, R., Suzuki, T., Sato, T., Kubosaki, A., Suzuki, M., Kawaji, H., Forrest, A. R. R., Hayashizaki, Y., FANTOM Consortium, Shin, J. W., & Suzuki, H.
Affiliations
  • RIKEN (JP)
  • Chugai Pharmaceutical Co., Ltd. (Japan) (JP)
Corresponding author
  • Shin, Jay W.
  • Suzuki, Harukazu
ORCID
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2014-07-10
Volume
42
Issue
14
Pages
8905-8913
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
DOI
10.1093/nar/gku567
PMC
PMC4132712
OpenAlex
W2105553482
Cited by
39
References
4
Citations by year
2025: 2 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 3 · 2017: 4 · 2016: 4 · 2015: 2 · 2014: 1
FWCI
1.50
Type
journal article
Language
en
Open access
Licence
Locations
  • Nucleic Acids Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UWA Profiles and Research Repository (University of Western Australia) (submittedVersion, cc-by)
  • UWA Profiles and Research Repository (UWA) (submittedVersion, cc-by)
Funders
  • Ministry of Education, Culture, Sports, Science and Technology
  • Japan Society for the Promotion of Science (22710201)
  • RIKEN
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords
transcriptional regulatory networks, transdifferentiation, dermal fibroblasts, transcription factor knockdown, cellular reprogramming, adipogenesis, lipid droplets, PPARγ, CEBPA
MeSH terms
Adult, Cells, Cultured, Fibroblasts, Humans, Infant, Newborn, Transcription Factors, Adipocytes, RNA Interference, Gene Regulatory Networks, Cell Transdifferentiation, Transcriptome

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