Depletion of Mageb16 induces differentiation of pluripotent stem cells predominantly into mesodermal derivatives

Gaspar, John Antonydas; Srinivasan, Sureshkumar Perumal; Sureshkumar, Poornima; Doss, Michael Xavier; Hescheler, Jürgen; Papadopoulos, Symeon; Sachinidis, Agapios

doi:10.1038/s41598-017-14561-z

Cited by 7 publications

(6 citation statements)

References 27 publications

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“…Functional genetic studies suggest that the SPATA16 molecules play important roles in human sperm formation and male fertility [51,60]. Recent studies suggest that at least MAGEB16 is potentially involved in spermatogenesis [48,50], and possibly TMCO5A, as shown in the rat model [49]. Furthermore, POTED belongs to the primatespecific POTE gene family.…”

Section: Discussionmentioning

confidence: 99%

“…Few biological data are available for most of these genes. The GO analysis and the literature suggest that the proteins of the SPATA16 and possibly of TMCO5A and MAGEB16 are involved in spermatogenesis [47][48][49][50][51]. Furthermore, the POTED gene belongs to the primate-specific POTE gene family.…”

Section: Positive Diversifying Selection Of Testis-enriched Genes In mentioning

confidence: 99%

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Population-specific, recent positive directional selection suggests adaptation of human male reproductive genes to different environmental conditions

Schaschl

Wallner

2020

BMC Evol Biol

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Background: Recent human transcriptomic analyses revealed a very large number of testis-enriched genes, many of which are involved in spermatogenesis. This comprehensive transcriptomic data lead us to the question whether positive selection was a decisive force influencing the evolution and variability of testis-enriched genes in humans. We used two methodological approaches to detect different levels of positive selection, namely episodic positive diversifying selection (i.e., past selection) in the human lineage within primate phylogeny, potentially driven by sperm competition, and recent positive directional selection in contemporary human populations, which would indicate adaptation to different environments. Results: In the human lineage (after correction for multiple testing) we found that only the gene TULP2, for which no functional data are yet available, is subject to episodic positive diversifying selection. Using less stringent statistical criteria (uncorrected p-values), also the gene SPATA16, which has a pivotal role in male fertility and for which episodes of adaptive evolution have been suggested, also displays a putative signal of diversifying selection in the human branch. At the same time, we found evidence for recent positive directional selection acting on several human testis-enriched genes (MORC1, SLC9B1, ROPN1L, DMRT1, PLCZ1, RNF17, FAM71D and WBP2NL) that play important roles in human spermatogenesis and fertilization. Most of these genes are population-specifically under positive selection. Conclusion: Episodic diversifying selection, possibly driven by sperm competition, was not an important force driving the evolution of testis-enriched genes in the human lineage. Population-specific, recent positive directional selection suggests an adaptation of male reproductive genes to different environmental conditions. Positive selection acts on eQTLS and sQTLs, indicating selective effects on important gene regulatory functions. In particular, the transcriptional diversity regulated by sQTLs in testis-enriched genes may be important for spermatocytes to respond to environmental and physiological stress.

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Section: Discussionmentioning

confidence: 99%

Section: Positive Diversifying Selection Of Testis-enriched Genes In mentioning

confidence: 99%

Population-specific, recent positive directional selection suggests adaptation of human male reproductive genes to different environmental conditions

Schaschl

Wallner

2020

BMC Evol Biol

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“…Thus, difference in the expression levels of Mage-a2 detected in this work between mouse pluripotent and teratocarcinoma cells, likewise in MAGE-A2 expression between human ESCs and ECCs [34], may be characteristic for teratocarcinoma cells and contribute to their malignant phenotype with imbalance of proliferation and differentiation potentials. Additionally, the over-expression of MAGEA2 was found to intensify the self-renewal and to repress differentiation efficiency of human induced pluripotent stem cells while depletion of Mageb16 in mouse ESCs induced more effective differentiation [49, 50]. In cancer cells, MAGEA2 and MAGEA6 promote cell growth and survival by targeting tumor suppressor protein AMP-activated protein kinase and preventing of ubiquitination and proteasome-dependent degradation, and acetylating p53 through histone deacetylase recruitment [6, 51–54].…”

Section: Discussionmentioning

confidence: 99%

“…Predominant MAGE-A8 expression was also detected in the early differentiating mesenchymal, neuroectodermal and extraendodermal cells derived from human ESCs [34], indicating a possible common mechanism with MAGE-A8/Mage-a8 regulating the early differentiation stages of mouse and human pluripotent stem cells. Mage-l2 has been shown to involve in neural development and the regulation of male and female reproductive functions [21, 68–70], while Mage-b16 (cluster 4) expression was associated with the expression of genes regulating pluripotency, spermatogenesis and somatic lineage differentiation [50]. Noteworthy, the differential expression of both classes of Mage family genes was detected during development of reproductive and somatic derivatives in mice (Mouse Genome Informatics: references: J:262143; J:255000; J:257298; J:257299).…”

Section: Discussionmentioning

confidence: 99%

Expression dynamics of Mage family genes during self-renewal and differentiation of mouse pluripotent stem and teratocarcinoma cells

2019

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The biological roles of cancer-testis antigens of the Melanoma antigen (Mage) family in mammalian development, stem cell differentiation and carcinogenesis are largely unknown. In order to understand the involvement of the Mage family genes in maintenance of normal and cancer stem cells, the expression patterns of Mage-a, Mage-b, Mage-d, Mage-e, Mage-h and Mage-l gene subfamilies were analyzed during the self-renewal and differentiation of mouse pluripotent stem and teratocarcinoma cells. Clustering analysis based on the gene expression profiles of undifferentiated and differentiating cell populations revealed strong correlations between Mage expression patterns and differentiation and malignant states. Gene co-expression analysis disclosed the potential contributions of Mage family members in self-renewal and differentiation of pluripotent stem and teratocarcinoma cells. Two gene clusters including Mage-a4 and Mage-a8, Mageb1, Mage-d1, Mage-d2, Mage-e1, Mage-l2 were identified as functional antagonists with opposing roles in the regulation of proliferation and differentiation of mouse pluripotent stem and teratocarcinoma cells. The identified aberrant expression patterns of Mage-a2, Mage-a6, Mage-b4, Mageb-16 and Mage-h1 in teratocarcinoma cells can be considered as specific teratocarcinoma biomarkers promoted the malignant phenotype. Our study first provides a model for the involvement of Mage family members in regulatory networks during the self-renewal and early differentiation of normal and cancerous stem cells for further research of the predicted functional modules and the development of new cancer treatment strategies.

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“…For microarray studies, undifferentiated C2 fl/fl [Cre] ESC (treated with ethanol for 48 h, corresponding to the onset of differentiation-D0) and C2 fl/fl [Cre] ESC differentiated by hanging drop/embryoid bodies formation until D4 after ethanol or 4HT treatment for 48 h at the onset of differentiation were collected. RNA preparation, microarray hybridization to Mouse Genome 430 2.0 arrays (Affymetrix), as well as quality control of matrices, raw data background correction, summary and normalization of microarray data, and a PCA to evaluate transcriptomic variability between the samples obtained from ESC at D0 and differentiated cells at D4 upon treatment of ethanol or 4HT were performed as previously described 29 . Differential expression was determined through application of an empirical Bayes linear model, and the significance of the changes was adjusted using Benjamini–Hochberg method, with adjusted p < 0.05 considered statistically significant.…”

Section: Methodsmentioning

confidence: 99%

Exogenous WNT5A and WNT11 proteins rescue CITED2 dysfunction in mouse embryonic stem cells and zebrafish morphants

et al. 2019

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Mutations and inadequate methylation profiles of CITED2 are associated with human congenital heart disease (CHD). In mouse, Cited2 is necessary for embryogenesis, particularly for heart development, and its depletion in embryonic stem cells (ESC) impairs cardiac differentiation. We have now determined that Cited2 depletion in ESC affects the expression of transcription factors and cardiopoietic genes involved in early mesoderm and cardiac specification. Interestingly, the supplementation of the secretome prepared from ESC overexpressing CITED2, during the onset of differentiation, rescued the cardiogenic defects of Cited2 -depleted ESC. In addition, we demonstrate that the proteins WNT5A and WNT11 held the potential for rescue. We also validated the zebrafish as a model to investigate cited2 function during development. Indeed, the microinjection of morpholinos targeting cited2 transcripts caused developmental defects recapitulating those of mice knockout models, including the increased propensity for cardiac defects and severe death rate. Importantly, the co-injection of anti- cited2 morpholinos with either CITED2 or WNT5A and WNT11 recombinant proteins corrected the developmental defects of Cited2-morphants. This study argues that defects caused by the dysfunction of Cited2 at early stages of development, including heart anomalies, may be remediable by supplementation of exogenous molecules, offering the opportunity to develop novel therapeutic strategies aiming to prevent CHD.

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Depletion of Mageb16 induces differentiation of pluripotent stem cells predominantly into mesodermal derivatives

Cited by 7 publications

References 27 publications

Population-specific, recent positive directional selection suggests adaptation of human male reproductive genes to different environmental conditions

Population-specific, recent positive directional selection suggests adaptation of human male reproductive genes to different environmental conditions

Expression dynamics of Mage family genes during self-renewal and differentiation of mouse pluripotent stem and teratocarcinoma cells

Exogenous WNT5A and WNT11 proteins rescue CITED2 dysfunction in mouse embryonic stem cells and zebrafish morphants

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