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Article ; Online: Characterization of Alternative Splicing in High-Risk Wilms' Tumors.

Trink, Yaron / Urbach, Achia / Dekel, Benjamin / Hohenstein, Peter / Goldberger, Jacob / Kalisky, Tomer

International journal of molecular sciences

2024 Volume 25, Issue 8

Abstract: The significant heterogeneity of Wilms' tumors between different patients is thought to arise from genetic and epigenetic distortions that occur during various stages of fetal kidney development in a way that is poorly understood. To address this, we ... ...

Abstract	The significant heterogeneity of Wilms' tumors between different patients is thought to arise from genetic and epigenetic distortions that occur during various stages of fetal kidney development in a way that is poorly understood. To address this, we characterized the heterogeneity of alternative mRNA splicing in Wilms' tumors using a publicly available RNAseq dataset of high-risk Wilms' tumors and normal kidney samples. Through Pareto task inference and cell deconvolution, we found that the tumors and normal kidney samples are organized according to progressive stages of kidney development within a triangle-shaped region in latent space, whose vertices, or "archetypes", resemble the cap mesenchyme, the nephrogenic stroma, and epithelial tubular structures of the fetal kidney. We identified a set of genes that are alternatively spliced between tumors located in different regions of latent space and found that many of these genes are associated with the epithelial-to-mesenchymal transition (EMT) and muscle development. Using motif enrichment analysis, we identified putative splicing regulators, some of which are associated with kidney development. Our findings provide new insights into the etiology of Wilms' tumors and suggest that specific splicing mechanisms in early stages of development may contribute to tumor development in different patients.
MeSH term(s)	Wilms Tumor/genetics ; Wilms Tumor/pathology ; Humans ; Alternative Splicing ; Kidney Neoplasms/genetics ; Kidney Neoplasms/pathology ; Epithelial-Mesenchymal Transition/genetics ; Gene Expression Regulation, Neoplastic ; Kidney/metabolism ; Kidney/pathology
Language	English
Publishing date	2024-04-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25084520
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Article ; Online: Characterization of Continuous Transcriptional Heterogeneity in High-Risk Blastemal-Type Wilms' Tumors Using Unsupervised Machine Learning.

Trink, Yaron / Urbach, Achia / Dekel, Benjamin / Hohenstein, Peter / Goldberger, Jacob / Kalisky, Tomer

International journal of molecular sciences

2023 Volume 24, Issue 4

Abstract: Wilms' tumors are pediatric malignancies that are thought to arise from faulty kidney development. They contain a wide range of poorly differentiated cell states resembling various distorted developmental stages of the fetal kidney, and as a result, ... ...

Abstract	Wilms' tumors are pediatric malignancies that are thought to arise from faulty kidney development. They contain a wide range of poorly differentiated cell states resembling various distorted developmental stages of the fetal kidney, and as a result, differ between patients in a continuous manner that is not well understood. Here, we used three computational approaches to characterize this continuous heterogeneity in high-risk blastemal-type Wilms' tumors. Using Pareto task inference, we show that the tumors form a triangle-shaped continuum in latent space that is bounded by three tumor archetypes with "stromal", "blastemal", and "epithelial" characteristics, which resemble the un-induced mesenchyme, the cap mesenchyme, and early epithelial structures of the fetal kidney. By fitting a generative probabilistic "grade of membership" model, we show that each tumor can be represented as a unique mixture of three hidden "topics" with blastemal, stromal, and epithelial characteristics. Likewise, cellular deconvolution allows us to represent each tumor in the continuum as a unique combination of fetal kidney-like cell states. These results highlight the relationship between Wilms' tumors and kidney development, and we anticipate that they will pave the way for more quantitative strategies for tumor stratification and classification.
MeSH term(s)	Child ; Humans ; Kidney Neoplasms/pathology ; Unsupervised Machine Learning ; Wilms Tumor ; Kidney/pathology
Language	English
Publishing date	2023-02-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24043532
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Article ; Online: Apoptosis induction by the stem cell factor LIN28A.

Attali-Padael, Yael / Armon, Leah / Urbach, Achia

Biology of the cell

2021 Volume 113, Issue 11, Page(s) 450–457

Abstract: Background information: Lin28A and its paralog Lin28B are RNA binding proteins expressed in stem and progenitor cells, regulating the balance between their proliferation and differentiation. In-vivo and in-vitro experiments have shown that ... ...

Abstract	Background information: Lin28A and its paralog Lin28B are RNA binding proteins expressed in stem and progenitor cells, regulating the balance between their proliferation and differentiation. In-vivo and in-vitro experiments have shown that overexpression of these genes leads to abnormal cell proliferation, which results in many cases in cell transformation and tumor formation. Results: Here we show, for the first time, that Lin28A overexpression can also lead to the opposite effect, i.e. apoptosis induction. We further demonstrate that this effect is specific to Lin28A but not to Lin28B and that it is mediated via the Let-7 independent pathway in a complex mechanism that involves at least several proteins. Conclusions and significance: This unexpected observation suggests that cell fate regulation by Lin28 is dependent on a specific cellular/genetic context. Unraveling the cellular and molecular mechanisms underlying this Lin28A overexpression effect may pave the way for novel tumor therapeutic strategies, as Lin28 is commonly expressed in many types of tumors but not in most normal adult cells.
MeSH term(s)	Apoptosis ; Cell Differentiation ; MicroRNAs/genetics ; RNA-Binding Proteins/genetics ; Stem Cell Factor
Chemical Substances	MicroRNAs ; RNA-Binding Proteins ; Stem Cell Factor
Language	English
Publishing date	2021-09-07
Publishing country	England
Document type	Journal Article
ZDB-ID	245745-3
ISSN	1768-322X ; 0399-0311 ; 0248-4900
ISSN (online)	1768-322X
ISSN	0399-0311 ; 0248-4900
DOI	10.1111/boc.202100011
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Article ; Online: Heterochronic regulation of lung development

Komarovsky Gulman, Nelly / Armon, Leah / Shalit, Tali / Urbach, Achia

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2019 Volume 33, Issue 11, Page(s) 12008–12018

Abstract: The heterochronic gene Lin28 regulates diverse developmental processes. It was shown previously that global Lin28A overexpression during mouse embryogenesis results in perinatal lethality. However, the reason for this early lethality has not been ... ...

Abstract	The heterochronic gene Lin28 regulates diverse developmental processes. It was shown previously that global Lin28A overexpression during mouse embryogenesis results in perinatal lethality. However, the reason for this early lethality has not been elucidated. Here, we showed that Lin28A overexpression prevents normal lung development
MeSH term(s)	Animals ; Cell Differentiation/genetics ; Cell Proliferation/genetics ; Cluster Analysis ; Embryonic Development/genetics ; Female ; Gene Expression Profiling/methods ; Gene Expression Regulation, Developmental ; Lung/cytology ; Lung/embryology ; Lung/metabolism ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/metabolism ; Mice, Transgenic ; MicroRNAs/genetics ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Signal Transduction/genetics ; Time Factors
Chemical Substances	Lin-28 protein, mouse ; MicroRNAs ; RNA-Binding Proteins ; mirnlet7 microRNA, mouse
Language	English
Publishing date	2019-08-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.201802702R
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Zs.A 2266: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Generation and characterization of iPSC lines from two nuclear envelopathy patients with a homozygous nonsense mutation in the TOR1AIP1 gene.

Ben-Haim, Yam / Armon, Leah / Fichtman, Boris / Epshtein, Irina / Spiegel, Ronen / Harel, Amnon / Urbach, Achia

Stem cell research

2021 Volume 56, Page(s) 102539

Abstract: LAP1 is an inner nuclear membrane protein encoded by TOR1AIP1. A homozygous c.961C > T loss of function mutation in TOR1AIP1 that affects both isoforms of LAP1 was recently described. This mutation leads to the development of a severe multisystemic ... ...

Abstract	LAP1 is an inner nuclear membrane protein encoded by TOR1AIP1. A homozygous c.961C > T loss of function mutation in TOR1AIP1 that affects both isoforms of LAP1 was recently described. This mutation leads to the development of a severe multisystemic nuclear envelopathy syndrome. Here we describe the generation and characterization of two human induced pluripotent stem cell (hiPSC) lines derived from skin fibroblasts of two patients carrying the homozygous c.961C > T mutation. These novel lines can be used as a powerful tool to investigate the molecular mechanism by which LAP1 deficiency leads to the development of this severe hereditary disorder.
MeSH term(s)	Codon, Nonsense/genetics ; Cytoskeletal Proteins/genetics ; Humans ; Induced Pluripotent Stem Cells ; Membrane Proteins/genetics ; Mutation/genetics ; Nuclear Envelope/pathology ; Protein Isoforms/genetics
Chemical Substances	Codon, Nonsense ; Cytoskeletal Proteins ; Membrane Proteins ; Protein Isoforms ; TOR1AIP1 protein, human
Language	English
Publishing date	2021-09-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2393143-7
ISSN	1876-7753 ; 1873-5061
ISSN (online)	1876-7753
ISSN	1873-5061
DOI	10.1016/j.scr.2021.102539
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Article: Comparing ESC and iPSC-Based Models for Human Genetic Disorders.

Halevy, Tomer / Urbach, Achia

Journal of clinical medicine

2014 Volume 3, Issue 4, Page(s) 1146–1162

Abstract: Traditionally, human disorders were studied using animal models or somatic cells taken from patients. Such studies enabled the analysis of the molecular mechanisms of numerous disorders, and led to the discovery of new treatments. Yet, these systems are ... ...

Abstract	Traditionally, human disorders were studied using animal models or somatic cells taken from patients. Such studies enabled the analysis of the molecular mechanisms of numerous disorders, and led to the discovery of new treatments. Yet, these systems are limited or even irrelevant in modeling multiple genetic diseases. The isolation of human embryonic stem cells (ESCs) from diseased blastocysts, the derivation of induced pluripotent stem cells (iPSCs) from patients' somatic cells, and the new technologies for genome editing of pluripotent stem cells have opened a new window of opportunities in the field of disease modeling, and enabled studying diseases that couldn't be modeled in the past. Importantly, despite the high similarity between ESCs and iPSCs, there are several fundamental differences between these cells, which have important implications regarding disease modeling. In this review we compare ESC-based models to iPSC-based models, and highlight the advantages and disadvantages of each system. We further suggest a roadmap for how to choose the optimal strategy to model each specific disorder.
Language	English
Publishing date	2014-10-24
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm3041146
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Article ; Online: Comparing ESC and iPSC—Based Models for Human Genetic Disorders

Tomer Halevy / Achia Urbach

Journal of Clinical Medicine, Vol 3, Iss 4, Pp 1146-

2014 Volume 1162

Abstract	Traditionally, human disorders were studied using animal models or somatic cells taken from patients. Such studies enabled the analysis of the molecular mechanisms of numerous disorders, and led to the discovery of new treatments. Yet, these systems are limited or even irrelevant in modeling multiple genetic diseases. The isolation of human embryonic stem cells (ESCs) from diseased blastocysts, the derivation of induced pluripotent stem cells (iPSCs) from patients’ somatic cells, and the new technologies for genome editing of pluripotent stem cells have opened a new window of opportunities in the field of disease modeling, and enabled studying diseases that couldn’t be modeled in the past. Importantly, despite the high similarity between ESCs and iPSCs, there are several fundamental differences between these cells, which have important implications regarding disease modeling. In this review we compare ESC-based models to iPSC-based models, and highlight the advantages and disadvantages of each system. We further suggest a roadmap for how to choose the optimal strategy to model each specific disorder.
Keywords	embryonic stem cells (ESCs) ; induced pluripotent stem cells (iPSCs) ; disease modeling ; Medicine ; R
Subject code	610
Language	English
Publishing date	2014-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Human Pluripotent Stem Cell Fate Regulation by SMARCB1.

Carmel-Gross, Ilana / Levy, Etgar / Armon, Leah / Yaron, Orly / Waldman Ben-Asher, Hiba / Urbach, Achia

Stem cell reports

2020 Volume 15, Issue 5, Page(s) 1037–1046

Abstract: Epigenetic regulation by the SWI/SNF complex is essential for normal self-renewal capacity and pluripotency of human pluripotent stem cells (hPSCs). It has been shown that different subunits of the complex have a distinct role in this regulation. ... ...

Abstract	Epigenetic regulation by the SWI/SNF complex is essential for normal self-renewal capacity and pluripotency of human pluripotent stem cells (hPSCs). It has been shown that different subunits of the complex have a distinct role in this regulation. Specifically, the SMARCB1 subunit has been shown to regulate the activity of enhancers in diverse types of cells, including hPSCs. Here, we report the establishment of conditional hPSC lines, enabling control of SMARCB1 expression from complete loss of function to significant overexpression. Using this system, we show that any deviation from normal SMARCB1 expression leads to cell differentiation. We further found that SMARCB1 expression is not required for differentiation of hPSCs into progenitor cells, but rather for later stages of differentiation. Finally, we identify SMARCB1 as a critical player in regulation of cell-cell and cell-ECM interactions in hPSCs and show that this regulation is mediated at least in part by the WNT pathway.
MeSH term(s)	Cell Communication ; Cell Differentiation ; Cell Line ; Epigenesis, Genetic ; Extracellular Matrix/metabolism ; Gene Expression Regulation ; Human Embryonic Stem Cells/cytology ; Humans ; Induced Pluripotent Stem Cells/cytology ; SMARCB1 Protein/genetics ; SMARCB1 Protein/metabolism ; Stem Cells/metabolism ; Wnt Signaling Pathway
Chemical Substances	SMARCB1 Protein ; SMARCB1 protein, human
Language	English
Publishing date	2020-10-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2720528-9
ISSN	2213-6711 ; 2213-6711
ISSN (online)	2213-6711
ISSN	2213-6711
DOI	10.1016/j.stemcr.2020.10.002
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Article ; Online: Geometry of Gene Expression Space of Wilms' Tumors From Human Patients.

Trink, Ariel / Kanter, Itamar / Pode-Shakked, Naomi / Urbach, Achia / Dekel, Benjamin / Kalisky, Tomer

Neoplasia (New York, N.Y.)

2018 Volume 20, Issue 8, Page(s) 871–881

Abstract: Wilms' tumor is a pediatric malignancy that is thought to originate from faulty kidney development during the embryonic stage. However, there is a large variation between tumors from different patients in both histology and gene expression that is not ... ...

Abstract	Wilms' tumor is a pediatric malignancy that is thought to originate from faulty kidney development during the embryonic stage. However, there is a large variation between tumors from different patients in both histology and gene expression that is not well characterized. Here we use a meta-analysis of published microarray datasets to show that Favorable Histology Wilms' Tumors (FHWT's) fill a triangle-shaped continuum in gene expression space of which the vertices represent three idealized "archetypes". We show that these archetypes have predominantly renal blastemal, stromal, and epithelial characteristics and that they correlate well with the three major lineages of the developing embryonic kidney. Moreover, we show that advanced stage tumors shift towards the renal blastemal archetype. These results illustrate the potential of this methodology for characterizing the cellular composition of Wilms' tumors and for assessing disease progression.
MeSH term(s)	Disease Progression ; Gene Expression/genetics ; Gene Expression Regulation, Neoplastic/genetics ; Genes, Wilms Tumor ; Humans ; Kidney/metabolism ; Kidney/pathology ; Kidney Neoplasms/genetics ; Kidney Neoplasms/pathology ; Wilms Tumor/genetics ; Wilms Tumor/pathology
Language	English
Publishing date	2018-07-18
Publishing country	United States
Document type	Journal Article ; Meta-Analysis
ZDB-ID	1483840-0
ISSN	1476-5586 ; 1522-8002
ISSN (online)	1476-5586
ISSN	1522-8002
DOI	10.1016/j.neo.2018.06.006
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Zs.A 5203: Show issues

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Article ; Online: Characterization of alternative mRNA splicing in cultured cell populations representing progressive stages of human fetal kidney development.

Wineberg, Yishay / Kanter, Itamar / Ben-Haim, Nissim / Pode-Shakked, Naomi / Bucris, Efrat / Bar-Lev, Tali Hana / Oriel, Sarit / Reinus, Harel / Yehuda, Yishai / Gershon, Rotem / Shukrun, Rachel / Bar-Lev, Dekel Dov / Urbach, Achia / Dekel, Benjamin / Kalisky, Tomer

Scientific reports

2022 Volume 12, Issue 1, Page(s) 19548

Abstract: Nephrons are the functional units of the kidney. During kidney development, cells from the cap mesenchyme-a transient kidney-specific progenitor state-undergo a mesenchymal to epithelial transition (MET) and subsequently differentiate into the various ... ...

Abstract	Nephrons are the functional units of the kidney. During kidney development, cells from the cap mesenchyme-a transient kidney-specific progenitor state-undergo a mesenchymal to epithelial transition (MET) and subsequently differentiate into the various epithelial cell types that create the tubular structures of the nephron. Faults in this transition can lead to a pediatric malignancy of the kidney called Wilms' tumor that mimics normal kidney development. While human kidney development has been characterized at the gene expression level, a comprehensive characterization of alternative splicing is lacking. Therefore, in this study, we performed RNA sequencing on cell populations representing early, intermediate, and late developmental stages of the human fetal kidney, as well as three blastemal-predominant Wilms' tumor patient-derived xenografts. Using this newly generated RNAseq data, we identified a set of transcripts that are alternatively spliced between the different developmental stages. Moreover, we found that cells from the earliest developmental stage have a mesenchymal splice-isoform profile that is similar to that of blastemal-predominant Wilms' tumor xenografts. RNA binding motif enrichment analysis suggests that the mRNA binding proteins ESRP1, ESRP2, RBFOX2, and QKI regulate alternative mRNA splicing during human kidney development. These findings illuminate new molecular mechanisms involved in human kidney development and pediatric kidney cancer.
MeSH term(s)	Humans ; Child ; Alternative Splicing ; RNA, Messenger/genetics ; Wilms Tumor/genetics ; Wilms Tumor/pathology ; Kidney Neoplasms/pathology ; Kidney/pathology ; Cells, Cultured ; RNA Splicing Factors/genetics ; Repressor Proteins/genetics
Chemical Substances	RNA, Messenger ; RBFOX2 protein, human ; RNA Splicing Factors ; Repressor Proteins
Language	English
Publishing date	2022-11-15
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-24147-z
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