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

Tomaru, Yasuhiro, Hasegawa, Ryota, Suzuki, Takahiro, Sato, Taiji, Kubosaki, Atsutaka, Suzuki, Masanori, Kawaji, Hideya, Forrest, Alistair R. R., Hayashizaki, Yoshihide, FANTOM Consortium, Shin, Jay W., Suzuki, Harukazu, Beckhouse, Anthony, Wells, Christine, Vijayan, Dipti, Wolvetang, Ernst, Hitchens, Kelly, Fearnley, Liam, Kenna, Tony, Blumenthal, Antje, Briggs, James, Ovchinnikov, Dmitry, Le Cao, Kim-Anh, Mason, Elizabeth and Nielsen, Lars (2014) A transient disruption of fibroblastic transcriptional regulatory network facilitates trans-differentiation. Nucleic Acids Research, 42 14: 8905-8913. doi:10.1093/nar/gku567

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Author Tomaru, Yasuhiro
Hasegawa, Ryota
Suzuki, Takahiro
Sato, Taiji
Kubosaki, Atsutaka
Suzuki, Masanori
Kawaji, Hideya
Forrest, Alistair R. R.
Hayashizaki, Yoshihide
FANTOM Consortium
Shin, Jay W.
Suzuki, Harukazu
Beckhouse, Anthony
Wells, Christine
Vijayan, Dipti
Wolvetang, Ernst
Hitchens, Kelly
Fearnley, Liam
Kenna, Tony
Blumenthal, Antje
Briggs, James
Ovchinnikov, Dmitry
Le Cao, Kim-Anh
Mason, Elizabeth
Nielsen, Lars
Total Author Count Override 262
Title A transient disruption of fibroblastic transcriptional regulatory network facilitates trans-differentiation
Journal name Nucleic Acids Research   Check publisher's open access policy
ISSN 0305-1048
1362-4962
Publication date 2014-01-01
Year available 2014
Sub-type Article (original research)
DOI 10.1093/nar/gku567
Open Access Status DOI
Volume 42
Issue 14
Start page 8905
End page 8913
Total pages 9
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Collection year 2015
Language eng
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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Non-UQ

 
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Created: Wed, 25 Mar 2015, 19:48:27 EST by Kylie Hengst on behalf of UQ Diamantina Institute