MeCP2 deficiency promotes cell reprogramming by stimulating IGF1/AKT/mTOR signaling and activating ribosomal protein-mediated cell cycle gene translation

Abstract

The generation of induced pluripotent stem cells (iPSCs) offers a great opportunity in research and regenerative medicine. The current poor efficiency and incomplete mechanistic understanding of the reprogramming process hampers the clinical application of iPSCs. MeCP2 connects histone modification and DNA methylation, which are key changes of somatic cell reprogramming. However, the role of MeCP2 in cell reprogramming has not been examined. In this study, we found that MeCP2 deficiency enhanced reprogramming efficiency and stimulated cell proliferation through regulating cell cycle protein expression in the early stage of reprogramming. MeCP2 deficiency enhanced the expression of ribosomal protein genes, thereby enhancing reprogramming efficiency through promoting the translation of cell cycle genes. In the end, MeCP2 deficiency stimulated IGF1/AKT/mTOR signaling and activated ribosomal protein gene expression. Taken together, our data indicate that MeCP2 deficiency promoted cell reprogramming through stimulating IGF1/AKT/mTOR signaling and activating ribosomal protein-mediated cell cycle gene translation in the early stage of reprogramming.

Accelerated Hyper-Maturation of Parvalbumin Circuits in the Absence of MeCP2

“…MeCP2 is a multifunctional chromatin protein that regulates long gene expression (Sugino et al 2014;Gabel et al 2015) by either repressing or activating transcription or by functioning at a post-transcriptional level (Chahrour et al 2008;Lyst and Bird 2015). Recently, it has also been demonstrated that MeCP2 promotes cell reprogramming and stimulates cell proliferation through regulating cell cycle protein expression (Zhang et al 2018).…”

Ribosomes: An Exciting Avenue in Stem Cell Research

“…The phosphatidylinositol-3-kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR) signaling pathways (PI3K/Akt/mTOR) are pivotal for cell growth and survival [141][142][143][144]. Cells can be reprogrammed by activating IGF1/AKT/mTOR signaling and increasing the translation of RPs in cells depleted of MeCP2 (Figure 2) [145]. mTOR phosphorylates downstream effectors, including S6 kinase (s6K) [146] and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) [147,148].…”