1.Suppression of the ERK–SRF axis facilitates somatic cell reprogramming
Sejong HUH ; Hwa Ryung SONG ; Geuk Rae JEONG ; Hyejin JANG ; Nan Hee SEO ; Ju Hyun LEE ; Ji Yeun YI ; Byongsun LEE ; Hyun Woo CHOI ; Jeong Tae DO ; Jin Su KIM ; Soo Hong LEE ; Jae Won JUNG ; Taekyu LEE ; Jaekyung SHIM ; Myung Kwan HAN ; Tae Hee LEE
Experimental & Molecular Medicine 2018;50(2):e448-
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.
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