MicroRNA Expression Patterns and Function in Endodermal Differentiation of Human Embryonic Stem Cells

Tzur, Galit; Levy, Asaf; Meiri, Eti; Barad, Omer; Spector, Yael; Bentwich, Zvi; Mizrahi, Lina; Katzenellenbogen, Mark; Ben-Shushan, Etti; Reubinoff, Benjamin; Galun, Eithan

doi:10.1371/journal.pone.0003726

Cited by 106 publications

(91 citation statements)

References 61 publications

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“…Interestingly, miR-10a mimic per se cannot drive SMC differentiation in the absence of RA treatment (data no shown), which implies that miR-10a up-regulation is elegantly integrated in harmony with other regulatory mechanisms operating during RA-induced SMC differentiation. As previously reported (35,(42)(43)(44), there is a list of miRs that show the same dynamic change as miR-10a during the differentiation of ESCs. More studies are needed to unravel the function of these miRs during this differentiation process.…”

Section: Discussionsupporting

confidence: 71%

“…The function of miR-10a has been indicated in apoptosis (32), protein synthesis (33), embryo development and differentiation (34,35), hematopoietic stem cell mobilization (36), inflammation (37), and various tumorigenesis including hematopoietic (38,39), liver (40), and urinary (41). Although miR-10a has been shown to be highly expressed in rat artery and slightly down-regulated by day 7 after angioplasty (18), there is no further literature available dissecting the intrinsic relationship between miR-10a and SMC differentia- *, p Ͻ 0.05.…”

Section: Discussionmentioning

confidence: 99%

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miR-10a Contributes to Retinoid Acid-induced Smooth Muscle Cell Differentiation

Huang

Xie

Sun

et al. 2010

Journal of Biological Chemistry

119

105

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MicroRNAs (miRs) have been reported to play a critical role in muscle differentiation and function. The purpose of this study is to determine the role of miRs during smooth muscle cell (SMC) differentiation from embryonic stem cells (ESCs). MicroRNA profiling showed that miR-10a expression is steadily increased during in vitro differentiation of mouse ESCs into SMCs. Lossof-function approaches using miR-10a inhibitors uncovered that miR-10a is a critical mediator for SMC lineage determination in our retinoic acid-induced ESC/SMC differentiation system. In addition, we have documented for the first time that histone deacetylase 4 is a novel target of miR-10a and mediates miR-10a function during ESC/SMC differentiation. To determine the molecular mechanism through which retinoic acid induced miR-10a expression, a consensus NF-B element was identified in the miR-10a gene promoter by bioinformatics analysis, and chromatin immunoprecipitation assay confirmed that NF-B could bind to this element. Finally, inhibition of NF-B nuclear translocation repressed miR-10a expression and decreased SMC differentiation from ESCs. Our data demonstrate for the first time that miR-10a is a novel regulator in SMC differentiation from ESCs. These studies suggest that miR-10a may play important roles in vascular biology and have implications for the diagnosis and treatment of vascular diseases.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

miR-10a Contributes to Retinoid Acid-induced Smooth Muscle Cell Differentiation

Huang

Xie

Sun

et al. 2010

Journal of Biological Chemistry

119

105

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“…TFs were associated with microRNAs following existence of predicted TF binding sites in the microRNA promoter as described. 40 The table lists only TFs which were associated with at least two coexpressed microRNAs. Several TFs in the same row indicate that all TFs are associated with the same microRNAs in that row.…”

Section: Discussionmentioning

confidence: 99%

“…Such coregulated groups can hint at a possible effect of upstream regulatory components. An analysis of predicted binding sites of transcription factors near the start sites of coregulated microRNA transcripts 40 generates a list of transcription factors that may be enriched for factors related to biological differences between the histological types 40 (Table 2). Given the underlying biological similarities between the tumor types (Figure 2), we decided to construct a classifier to identify kidney tumor subtype in two steps, following the binary structure 31 of the hierarchical clustering tree: the first step identifies whether the sample belongs to one pair of types (chromophobe, oncocytoma) or to the other pair (conventional, papillary); the second step decides between the two types in each pair.…”

Section: ) and Papillary Tumors (N ϭ 20)mentioning

confidence: 99%

Accurate Molecular Classification of Renal Tumors Using MicroRNA Expression

Fridman

Dotan

Barshack

et al. 2010

The Journal of Molecular Diagnostics

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103

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Subtypes of renal tumors have different genetic backgrounds, prognoses, and responses to surgical and medical treatment, and their differential diagnosis is a frequent challenge for pathologists. New biomarkers can help improve the diagnosis and hence the management of renal cancer patients. We extracted RNA from 71 formalin-fixed paraffin-embedded (FFPE) renal tumor samples and measured expression of more than 900 microRNAs using custom microarrays. Clustering revealed similarity in microRNA expression between oncocytoma and chromophobe subtypes as well as between conventional (clear-cell) and papillary tumors. By basing a classification algorithm on this structure, we followed inherent biological correlations and could achieve accurate classification using few microRNAs markers. We defined a two-step decision-tree classifier that uses expression levels of six microRNAs: the first step uses expression levels of hsa-miR-210 and hsa-miR-221 to distinguish between the two pairs of subtypes; the second step uses either hsa-miR-200c with hsa-miR-139-5p to identify oncocytoma from chromophobe, or hsa-miR-31 with hsa-miR-126 to identify conventional from papillary tumors. The classifier was tested on an independent set of FFPE tumor samples from 54 additional patients, and identified correctly 93% of the cases. Validation on qRT-PCR platform demonstrated high correlation with microarray results and accurate classification. MicroRNA expression profiling is a very effective molecular bioassay for classification of renal tumors and can offer a quantitative standardized complement to current methods of tumor classification.

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“…Previously, miRNA expression has been examined in murine and human ES cells using cloning, microarray, quantitative polymerase chain reaction (PCR), and deep sequencing technologies on selected cell lines [20][21][22][23][24][25][26][27][28][29]. These studies typically involve embryoid body (EB) formation as an intermediate step, and the differentiation protocols extend for several weeks.…”

Section: Establishment Of Induced Pluripotent Stem (Ips) Cell Linesmentioning

confidence: 99%

Characterization of microRNAs Involved in Embryonic Stem Cell States

Stadler

Ivanovska²,

Mehta

et al. 2010

Stem Cells and Development

154

167

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Studies of embryonic stem cells (ESCs) reveal that these cell lines can be derived from differing stages of embryonic development. We analyzed common changes in the expression of microRNAs (miRNAs) and mRNAs in 9 different human ESC (hESC) lines during early commitment and further examined the expression of key ESCenriched miRNAs in earlier developmental states in several species. We show that several previously defi ned hESC-enriched miRNA groups (the miR-302, -17, and -515 families, and the miR-371-373 cluster) and several other hESC-enriched miRNAs are down-regulated rapidly in response to differentiation. We further found that mRNAs up-regulated upon differentiation are enriched in potential target sites for these hESC-enriched miRNAs. Interestingly, we also observed that the expression of ESC-enriched miRNAs bearing identical seed sequences changed dynamically while the cells transitioned through early embryonic states. In human and monkey ESCs, as well as human-induced pluripotent stem cells (iPSCs), the miR-371-373 cluster was consistently up-regulated, while the miR-302 family was mildly down-regulated when the cells were chemically treated to regress to an earlier developmental state. Similarly, miR-302b, but not mmu-miR-295, was expressed at higher levels in murine epiblast stem cells (mEpiSC) as compared with an earlier developmental state, mouse ESCs. These results raise the possibility that the relative expression of related miRNAs might serve as diagnostic indicators in defi ning the developmental state of embryonic cells and other stem cell lines, such as iPSCs. These data also raise the possibility that miRNAs bearing identical seed sequences could have specifi c functions during separable stages of early embryonic development.

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MicroRNA Expression Patterns and Function in Endodermal Differentiation of Human Embryonic Stem Cells

Cited by 106 publications

References 61 publications

miR-10a Contributes to Retinoid Acid-induced Smooth Muscle Cell Differentiation

miR-10a Contributes to Retinoid Acid-induced Smooth Muscle Cell Differentiation

Accurate Molecular Classification of Renal Tumors Using MicroRNA Expression

Characterization of microRNAs Involved in Embryonic Stem Cell States

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