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Title: BMP Inhibition in Seminomas Initiates Acquisition of Pluripotency via NODAL Signaling Resulting in Reprogramming to an Embryonal Carcinoma
Author: Nettersheim, Daniel
Jostes, Sina
Sharma, Rakesh
Schneider, Simon
Hofmann, Andrea
Ferreira, Humberto J
Hoffmann, Per
Kristiansen, Glen
Esteller, Manel
Schorle, Hubert
Keywords: Expressió gènica
Microxips d'ADN
Gene expression
DNA microarrays
Issue Date: 30-Jul-2015
Abstract: Type II germ cell cancers (GCC) can be subdivided into seminomas and non-seminomas. Seminomas are similar to carcinoma in situ (CIS) cells, the common precursor of type II GCCs, with regard to epigenetics and expression, while embryonal carcinomas (EC) are totipotent and differentiate into teratomas, yolk-sac tumors and choriocarcinomas. GCCs can present as seminomas with a non-seminoma component, raising the question if a CIS gives rise to seminomas and ECs at the same time or whether seminomas can be repro- grammed to ECs. In this study, we utilized the seminoma cell line TCam-2 that acquires an EC-like status after xenografting into the murine flank as a model for a seminoma to EC tran- sition and screened for factors initiating and driving this process. Analysis of expression and DNA methylation dynamics during transition of TCam-2 revealed that many pluripotency- and reprogramming-associated genes were upregulated while seminoma-markers were downregulated. Changes in expression level of 53 genes inversely correlated to changes in DNA methylation. Interestingly, after xenotransplantation 6 genes ( GDF3 , NODAL , DNMT3B , DPPA3 , GAL , AK3L1 ) were rapidly induced, followed by demethylation of their genomic loci, suggesting that these 6 genes are poised for expression driving the repro- gramming. We demonstrate that inhibition of BMP signaling is the initial event in reprogram- ming, resulting in activation of the pluripotency-associated genes and NODAL signaling. We propose that reprogramming of seminomas to ECs is a multi-step process. Initially, the microenvironment causes inhibition of BMP signaling, leading to induction of NODAL sig- naling. During a maturation phase, a fast acting NODAL loop stimulates its own activity and temporarily inhibits BMP signaling. During the stabilization phase, a slow acting NODAL loop, involving WNTs re-establishes BMP signaling and the pluripotency circuitry. In parallel, DNMT3B-driven de novo methylation silences seminoma-associated genes and epigenetically fixes the EC state.
It is part of: Plos Genetics, 2015
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ISSN: 1553-7404
Appears in Collections:Articles publicats en revistes (Ciències Fisiològiques)

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