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Review
. 2014 Feb;24(2):143-60.
doi: 10.1038/cr.2013.151. Epub 2013 Nov 12.

Protein post-translational modifications and regulation of pluripotency in human stem cells

Yu-Chieh Wang  1 , Suzanne E Peterson  1 , Jeanne F Loring  1
Affiliations
Review

Protein post-translational modifications and regulation of pluripotency in human stem cells

Yu-Chieh Wang et al. Cell Res. 2014 Feb.

Abstract

Post-translational modifications (PTMs) are known to be essential mechanisms used by eukaryotic cells to diversify their protein functions and dynamically coordinate their signaling networks. Defects in PTMs have been linked to numerous developmental disorders and human diseases, highlighting the importance of PTMs in maintaining normal cellular states. Human pluripotent stem cells (hPSCs), including embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), are capable of self-renewal and differentiation into a variety of functional somatic cells; these cells hold a great promise for the advancement of biomedical research and clinical therapy. The mechanisms underlying cellular pluripotency in human cells have been extensively explored in the past decade. In addition to the vast amount of knowledge obtained from the genetic and transcriptional research in hPSCs, there is a rapidly growing interest in the stem cell biology field to examine pluripotency at the protein and PTM level. This review addresses recent progress toward understanding the role of PTMs (glycosylation, phosphorylation, acetylation and methylation) in the regulation of cellular pluripotency.

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Figures

Figure 1
Figure 1
Proteins in eukaryotic cells can be edited after translation by a wide variety of reversible and irreversible PTM mechanisms. The structure, stability and function of proteins in the cells can be dynamically altered by these PTMs. Four types of PTMs (glycosylation, phosphorylation, acetylation and methylation) are indicated by highlighted colors and primarily discussed in this review.
Figure 2
Figure 2
The derivation and differentiation of hPSCs. To obtain hESCs, the inner cell mass of a human blastocyst is isolated and cultured in vitro. To generate hiPSCs, differentiated cells are reprogrammed using a combination of different transcription factors (e.g., OCT4/POU5F1, SOX2, KLF4 and MYC) to establish cellular pluripotency in the cells. Both hESCs and hiPSCs are capable of differentiating into functional cells derived from all the three germ layers in embryos.
Figure 3
Figure 3
N-linked and O-linked protein glycosylation occurs in the ER and Golgi apparatus. The synthesis of precursor glycans (mannose-rich glycans) begins on the cytosolic face of the ER and is completed after the glycans are flipped into the ER lumen and further branched by adding more units of mannose and glucose. ER-resident glycosyltransferases (GTs) transfer the precursor glycans to asparagine residues on nascent proteins to form N-linked precursor glycans. When the proteins are transported into the Golgi apparatus, the N-linked precursor glycans are edited by Golgi-resident glycosidases (GSs) and GTs to form mature and structurally-diverse N-linked glycans. O-linked protein glycosylation is mainly performed by Golgi-resident GTs.
Figure 4
Figure 4
Cell signaling pathways governed by protein phosphorylation and critically involved in embryonic development and the regulation of pluripotent states in PSCs. Many growth factor receptors on the cell surface are receptor kinases. Upon ligand binding, these receptor kinases are fully activated and phosphorylate downstream, intracellular kinases to initiate phosphorylation signaling cascades that frequently regulate the translocation and activity of several transcription factors (e.g., Myc, β-Catenin and Smad proteins) and the expression of pluripotency- or differentiation-associated genes. These signal transduction pathways are highly interactive with each other and influenced by other proteins (e.g., HSPG) on the cell surface or in the microenvironment. Several protein phosphatases (e.g., PTEN and Shp2) that negatively control protein phosphorylation also play critical roles in the modulation of this signaling network and the differentiation potential of PSCs.
Figure 5
Figure 5
The antagonistic actions of HATs and HDACs are required for regulating the acetylation of histone and non-histone proteins in many types of mammalian cells, including mouse and human PSCs. HATs transfer acetyl groups onto proteins and HDACs remove the acetyl groups. The acetylation state of histones affects chromatin structure and dictates the accessibility of promoter regions to the transcriptional machinery and the activation of gene expression. In the pluripotent state, cells appear to have higher levels of global histone acetylation and chromatin accessibility for transcriptional machinery. The acetylation state and functions of many non-histone proteins are also controlled by HATs and HDACs.
Figure 6
Figure 6
The biochemical reactions of arginine and lysine methylation are catalyzed by protein arginine methyltransferases (PRMTs) and protein lysine methyltransferases (PKMTs) in cells. Depending on the number of methyl groups and types of methyltransferases that are involved in methylation, the reactions can result in the production of monomethylarginine, symmetric dimethylarginine, asymmetric dimethylarginine, monomethylated, dimethylated or trimethylated lysine in peptides. The asterisk indicates the ability of human type III PRMT (PRMT7) to convert arginine residues of proteins into monomethylarginines but not any form of dimethylarginines is debatable.
Figure 7
Figure 7
An illustration of amino acid residues where acetylation, methylation and phosphorylation frequently occur in core histones. Certain lysines (e.g., H3K4, H3K9 and H3K27) may be modified by either acetylation or methylation. Trimethylation of H3K4 and H3K27 gives rise to the bivalent chromatin marks found at the transcription start sites of many genes involved in lineage commitment and development in undifferentiated hPSCs. The majority of these bivalent marks resolve into one or the other at each particular gene during cell differentiation, depending on the expression state of the genes in differentiated derivatives. In general, genes induced during the differentiation of hPSCs retain the H3K4 methylation marks, and genes silenced during differentiation retain the H3K27 methylation marks. The phosphorylation of amino acid residues (e.g., H3S10 and H3S28) in close proximity to these lysines could influence their methylation-acetylation switch.
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