Journal Article

Suppression of the ERK–SRF axis facilitates somatic cell reprogramming

Lee, Tae-Hee, Lee, Soo-Hong, Seo, Nan-Hee, Lee, Ju-Hyun, Yi, Ji-Yeun, Choi, Hyun Woo, Shim, Jaekyung, Huh, Sejong, Jeong, Geuk-Rae, Do, Jeong Tae, Jang, Hyejin, Lee, Byongsun, Lee, Taekyu, Kim, Jin-Su, Song, Hwa-Ryung, Jung, Jae-Won, Han, Myung-Kwan

2018

Overview

The molecular mechanism underlying the initiation of somatic cell reprogramming into induced pluripotent stem cells (iPSCs) has not been well described. Thus, we generated single-cell-derived clones by using a combination of drug-inducible vectors encoding transcription factors (Oct4, Sox2, Klf4 and Myc) and a single-cell expansion strategy. This system achieved a high reprogramming efficiency after metabolic and epigenetic remodeling. Functional analyses of the cloned cells revealed that extracellular signal-regulated kinase (ERK) signaling was downregulated at an early stage of reprogramming and that its inhibition was a driving force for iPSC formation. Among the reprogramming factors, Myc predominantly induced ERK suppression. ERK inhibition upregulated the conversion of somatic cells into iPSCs through concomitant suppression of serum response factor (SRF). Conversely, SRF activation suppressed the reprogramming induced by ERK inhibition and negatively regulated embryonic pluripotency by inducing differentiation via upregulation of immediate early genes, such as c-Jun, c-Fos and EGR1. These data reveal that suppression of the ERK-SRF axis is an initial molecular event that facilitates iPSC formation and may be a useful surrogate marker for cellular reprogramming. Stem cells: A pivotal piece of the reprogramming process A biochemical signature for cellular ‘reprogramming’ could offer a helpful tool for researchers working in regenerative medicine. By forcing adult cells to express a key set of proteins, scientists can transform them into a state resembling embryonic stem cells. This process is notoriously inefficient. Researchers led by Tae-Hee Lee at Sejong University and Myung-Kwan Han at Chonbuk National University Medical School in South Korea have developed a cellular model that allowed them to identify barriers to reprogramming. They learned that a signaling molecule called ERK can block the stem cell transition early on. One protein responsible for cellular reprogramming, Myc, acts to inhibit ERK. The researchers identified a second protein in the ERK pathway which also interferes with reprogramming. They conclude that any cell reprogramming protocol must efficiently shut down this pathway to succeed.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 13 / 13/100 / 631/532/2435 / Animals / Biomarkers / Biomedical and Life Sciences / Biomedicine / c-Fos protein / c-Jun protein / Cell Line / Cell Transformation, Neoplastic / Cells, Cultured / Cellular Reprogramming - genetics / EGR-1 protein / Embryos / Extracellular signal-regulated kinase / Extracellular Signal-Regulated MAP Kinases - metabolism / Fibroblasts - cytology / Fibroblasts - metabolism / Gene Expression Regulation, Developmental / Genes, myc / Immediate-early proteins / Immunohistochemistry / Induced Pluripotent Stem Cells - cytology / Induced Pluripotent Stem Cells - metabolism / Inhibitory postsynaptic potentials / Kinases / KLF4 protein / Medical Biochemistry / Mice / Mice, Transgenic / Molecular Medicine / Myc protein / Oct-4 protein / Original / original-article / Phenotype / Phosphorylation / Pluripotency / Serum response factor / Serum Response Factor - metabolism / Signal Transduction / Somatic cells / Stem Cells / Transcription factors / Transcription Factors - genetics / Transcription Factors - metabolism