Proteomic and network analysis of proteins regulated by REX1 in human embryonic stem cells

Son, Mi‐Young; Kwak, Jae; Kim, Young-Dae; Cho, Yee Sook

doi:10.1002/pmic.201400510

Cited by 16 publications

(13 citation statements)

References 32 publications

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“…Details of the 2D and 3D culture methods used for HepaRG cells are provided in the http://onlinelibrary.wiley.com/doi/10.1002/hep.29324/suppinfo. The hESC cell line H9 (WiCell Research Institute, Madison, WI) and human iPSCs generated from fibroblasts as described were maintained on Matrigel (BD Biosciences, San Jose, CA)–coated dishes in mTeSR 1 medium (STEMCELL Technologies, Temecula, CA) …”

Section: Methodsmentioning

confidence: 99%

A liver‐specific gene expression panel predicts the differentiation status of in vitro hepatocyte models

et al. 2017

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Alternative cell sources, such as three‐dimensional organoids and induced pluripotent stem cell–derived cells, might provide a potentially effective approach for both drug development applications and clinical transplantation. For example, the development of cell sources for liver cell–based therapy has been increasingly needed, and liver transplantation is performed for the treatment for patients with severe end‐stage liver disease. Differentiated liver cells and three‐dimensional organoids are expected to provide new cell sources for tissue models and revolutionary clinical therapies. However, conventional experimental methods confirming the expression levels of liver‐specific lineage markers cannot provide complete information regarding the differentiation status or degree of similarity between liver and differentiated cell sources. Therefore, in this study, to overcome several issues associated with the assessment of differentiated liver cells and organoids, we developed a liver‐specific gene expression panel (LiGEP) algorithm that presents the degree of liver similarity as a “percentage.” We demonstrated that the percentage calculated using the LiGEP algorithm was correlated with the developmental stages of in vivo liver tissues in mice, suggesting that LiGEP can correctly predict developmental stages. Moreover, three‐dimensional cultured HepaRG cells and human pluripotent stem cell–derived hepatocyte‐like cells showed liver similarity scores of 59.14% and 32%, respectively, although general liver‐specific markers were detected. Conclusion: Our study describes a quantitative and predictive model for differentiated samples, particularly liver‐specific cells or organoids; and this model can be further expanded to various tissue‐specific organoids; our LiGEP can provide useful information and insights regarding the differentiation status of in vitro liver models. (Hepatology 2017;66:1662–1674).

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Section: Methodsmentioning

confidence: 99%

A liver‐specific gene expression panel predicts the differentiation status of in vitro hepatocyte models

et al. 2017

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“…The ratios describing the condition virulent/milder species of two comparative models ( R. slovaca / R. raoultii and R. conorii / R. massiliae ) were then log 2 transformed. Orthologous proteins with stringently defined fold change (FC ≥ 2) were considered to represent up-regulation (log 2 ratio ≥ 1) or down-regulation (log 2 ratio ≤ −1), whereas orthologous proteins with a FC < 2 were considered as equally regulated (Son et al, 2015). Proteins with FC = 2 included a minimal and a well-represented abundance value of 0.5 fmol.…”

Section: Methodsmentioning

confidence: 99%

Multi-omics Analysis Sheds Light on the Evolution and the Intracellular Lifestyle Strategies of Spotted Fever Group Rickettsia spp.

et al. 2017

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Arthropod-borne Rickettsia species are obligate intracellular bacteria which are pathogenic for humans. Within this genus, Rickettsia slovaca and Rickettsia conorii cause frequent and potentially severe infections, whereas Rickettsia raoultii and Rickettsia massiliae cause rare and milder infections. All four species belong to spotted fever group (SFG) rickettsiae. However, R. slovaca and R. raoultii cause scalp eschar and neck lymphadenopathy (SENLAT) and are mainly associated with Dermacentor ticks, whereas the other two species cause Mediterranean spotted fever (MSF) and are mainly transmitted by Rhipicephalus ticks. To identify the potential genes and protein profiles and to understand the evolutionary processes that could, comprehensively, relate to the differences in virulence and pathogenicity observed between these four species, we compared their genomes and proteomes. The virulent and milder agents displayed divergent phylogenomic evolution in two major clades, whereas either SENLAT or MSF disease suggests a discrete convergent evolution of one virulent and one milder agent, despite their distant genetic relatedness. Moreover, the two virulent species underwent strong reductive genomic evolution and protein structural variations, as well as a probable loss of plasmid(s), compared to the two milder species. However, an abundance of mobilome genes was observed only in the less pathogenic species. After infecting Xenopus laevis cells, the virulent agents displayed less up-regulated than down-regulated proteins, as well as less number of identified core proteins. Furthermore, their similar and distinct protein profiles did not contain some genes (e.g., ompA/B and rickA) known to be related to rickettsial adhesion, motility and/or virulence, but may include other putative virulence-, antivirulence-, and/or disease-related proteins. The identified evolutionary forces herein may have a strong impact on intracellular expressions and strategies in these rickettsiae, and that may contribute to the emergence of distinct virulence and diseases in humans. Thus, the current multi-omics data provide new insights into the evolution and fitness of SFG virulence and pathogenicity, and intracellular pathogenic bacteria.

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“…REX1 is expressed in several organs, including the brain, and plays an important role in differentiation, proliferation, and pluripotency. Recent proteomic and network analysis of proteins regulated by REX1 in human embryonic stem cells revealed that it affects several intracellular processes, including translation, regulation of mitochondrial processes, and specific differentiation [74], which might be affected in the patients with RLIM variants.…”

Section: Discussionmentioning

confidence: 99%

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

et al. 2018

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RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations. In contrast, 44 heterozygous female carriers have normal cognition and behavior, but eight showed mild physical features. All RLIM variants identified are missense changes cosegregating with the phenotype and predicted to affect protein function. Eight of the nine altered amino acids are conserved and lie either within a domain essential for binding interacting proteins or in the C-terminal RING finger catalytic domain. In vitro experiments revealed that these amino acid changes in the RLIM RING finger impaired RLIM ubiquitin ligase activity. In vivo experiments in rlim mutant zebrafish showed that wild type RLIM rescued the zebrafish rlim phenotype, whereas the patient-specific missense RLIM variants failed to rescue the phenotype and thus represent likely severe loss-of-function mutations. In summary, we identified a spectrum of RLIM missense variants causing syndromic XLID and affecting the ubiquitin ligase activity of RLIM, suggesting that enzymatic activity of RLIM is required for normal development, cognition and behavior.

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Proteomic and network analysis of proteins regulated by REX1 in human embryonic stem cells

Cited by 16 publications

References 32 publications

A liver‐specific gene expression panel predicts the differentiation status of in vitro hepatocyte models

A liver‐specific gene expression panel predicts the differentiation status of in vitro hepatocyte models

Multi-omics Analysis Sheds Light on the Evolution and the Intracellular Lifestyle Strategies of Spotted Fever Group Rickettsia spp.

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

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