RRC ID 45170
著者 Tomaru Y, Hasegawa R, Suzuki T, Sato T, Kubosaki A, Suzuki M, Kawaji H, Forrest AR, Hayashizaki Y, FANTOM Consortium, Shin JW, Suzuki H.
タイトル A transient disruption of fibroblastic transcriptional regulatory network facilitates trans-differentiation.
ジャーナル Nucleic Acids Res
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.
巻・号 42(14)
ページ 8905-13
公開日 2014-8-1
DOI 10.1093/nar/gku567
PII gku567
PMID 25013174
PMC PMC4132712
MeSH Adipocytes / cytology Adipocytes / metabolism Adult Cell Transdifferentiation / genetics* Cells, Cultured Fibroblasts / cytology Fibroblasts / metabolism* Gene Regulatory Networks* Humans Infant, Newborn RNA Interference Transcription Factors / antagonists & inhibitors Transcription Factors / metabolism* Transcriptome
IF 11.502
引用数 10
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
ヒト・動物細胞 NB1RGB(RCB0222)