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BMP Inhibition in Seminomas Initiates Acquisition of Pluripotency via NODAL Signaling Resulting in Reprogramming to an Embryonal Carcinoma.

Nettersheim D, Jostes S, Sharma R, Schneider S, Hofmann A, Ferreira HJ, Hoffmann P, Kristiansen G, Esteller MB, Schorle H - PLoS Genet. (2015)

Bottom Line: 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.We demonstrate that inhibition of BMP signaling is the initial event in reprogramming, resulting in activation of the pluripotency-associated genes and NODAL signaling.In parallel, DNMT3B-driven de novo methylation silences seminoma-associated genes and epigenetically fixes the EC state.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology, Department of Developmental Pathology, University Medical School, Bonn, Germany.

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 reprogrammed 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 transition 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 reprogramming. We demonstrate that inhibition of BMP signaling is the initial event in reprogramming, 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 signaling. 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.

No MeSH data available.


Related in: MedlinePlus

Model of the dynamics and molecular mechanisms during the SET.(A) Model summarizing the dynamics and events driving acquisition of pluripotency and epigenetic reprogramming of TCam-2 cells to an EC-like cell fate. (B) Models of the fast and slow acting NODAL feedback loop. Arrows indicate 'activation', T-shaped arrows indicate 'inhibition'.
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pgen.1005415.g006: Model of the dynamics and molecular mechanisms during the SET.(A) Model summarizing the dynamics and events driving acquisition of pluripotency and epigenetic reprogramming of TCam-2 cells to an EC-like cell fate. (B) Models of the fast and slow acting NODAL feedback loop. Arrows indicate 'activation', T-shaped arrows indicate 'inhibition'.

Mentions: Based on our findings, we propose a model in which the SET-reprogramming of xenografted TCam-2 is divided in three stages (initiation, maturation, stabilization) (Fig 6A) [80] [81]. The reprogramming is initiated by exogenous inhibition of BMP signaling causing rapid activation of NODAL. NODAL signaling establishes a fast acting autoregulatory loop (Fig 6B), leading to stimulation (CRIPTO /CRYPTIC) and limitation (LEFTY1 /2) of NODAL signaling and cell intrinsic suppression of BMP signaling. During this time, markers of pluripotency and reprogramming become upregulated and induction of DNMT3B initiates epigenetic remodeling. This phase we name the maturation phase. Thereafter, the slow acting NODAL feedback loop re-establishes BMP signaling to a level lower than in parental TCam-2, resulting in a balance between BMP and NODAL signaling and reinforcement of the acquired EC-like cell fate (the stabilization phase).


BMP Inhibition in Seminomas Initiates Acquisition of Pluripotency via NODAL Signaling Resulting in Reprogramming to an Embryonal Carcinoma.

Nettersheim D, Jostes S, Sharma R, Schneider S, Hofmann A, Ferreira HJ, Hoffmann P, Kristiansen G, Esteller MB, Schorle H - PLoS Genet. (2015)

Model of the dynamics and molecular mechanisms during the SET.(A) Model summarizing the dynamics and events driving acquisition of pluripotency and epigenetic reprogramming of TCam-2 cells to an EC-like cell fate. (B) Models of the fast and slow acting NODAL feedback loop. Arrows indicate 'activation', T-shaped arrows indicate 'inhibition'.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4520454&req=5

pgen.1005415.g006: Model of the dynamics and molecular mechanisms during the SET.(A) Model summarizing the dynamics and events driving acquisition of pluripotency and epigenetic reprogramming of TCam-2 cells to an EC-like cell fate. (B) Models of the fast and slow acting NODAL feedback loop. Arrows indicate 'activation', T-shaped arrows indicate 'inhibition'.
Mentions: Based on our findings, we propose a model in which the SET-reprogramming of xenografted TCam-2 is divided in three stages (initiation, maturation, stabilization) (Fig 6A) [80] [81]. The reprogramming is initiated by exogenous inhibition of BMP signaling causing rapid activation of NODAL. NODAL signaling establishes a fast acting autoregulatory loop (Fig 6B), leading to stimulation (CRIPTO /CRYPTIC) and limitation (LEFTY1 /2) of NODAL signaling and cell intrinsic suppression of BMP signaling. During this time, markers of pluripotency and reprogramming become upregulated and induction of DNMT3B initiates epigenetic remodeling. This phase we name the maturation phase. Thereafter, the slow acting NODAL feedback loop re-establishes BMP signaling to a level lower than in parental TCam-2, resulting in a balance between BMP and NODAL signaling and reinforcement of the acquired EC-like cell fate (the stabilization phase).

Bottom Line: 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.We demonstrate that inhibition of BMP signaling is the initial event in reprogramming, resulting in activation of the pluripotency-associated genes and NODAL signaling.In parallel, DNMT3B-driven de novo methylation silences seminoma-associated genes and epigenetically fixes the EC state.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology, Department of Developmental Pathology, University Medical School, Bonn, Germany.

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 reprogrammed 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 transition 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 reprogramming. We demonstrate that inhibition of BMP signaling is the initial event in reprogramming, 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 signaling. 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.

No MeSH data available.


Related in: MedlinePlus