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Expression data from cell lines forced expressed PGC7/Stella

ABSTRACT: Global DNA hypomethylation and DNA hypermethylation of promoter regions—including tumor suppressor genes—are frequently detected in human cancers. Although many studies have suggested a contribution to carcinogenesis, it is still unclear whether the aberrant DNA hypomethylation observed in tumors is a consequence or a cause of cancer. We found that overexpression of Stella (also known as PGC7, Dppa3), a maternal factor required for the maintenance of DNA methylation in early embryos, induced global DNA hypomethylation and transformation in NIH3T3 cells. This hypomethylation was due to the binding of Stella to Np95 (also known as Uhrf1, ICBP90) and the subsequent impairment of Dnmt1 localization. In addition, enforced expression of Stella enhanced the metastatic ability of B16 melanoma cells through the induction of metastasis-related genes by inducing DNA hypomethylation of their promoter regions. Such DNA hypomethylation itself causes cellular transformation and metastatic ability. These data provide new insight into the function of global DNA hypomethylation in carcinogenesis. We used microarrays to detail the global programme of gene expression by PGC7/Stella overexpression.

ORGANISM(S): Mus musculus

PROVIDER: GSE68837 | GEO | 2016/05/13

SECONDARY ACCESSION(S): PRJNA283868

REPOSITORIES: GEO

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Project description:Malignant (type II) testicular germ cell tumors (TGCT) are considered tumors of embryonic germ cell ancestry that diverge morphologically as seminoma (SE), and nonseminomas (NS), the latter including embryonal carcinoma (EC), teratoma (TE), yolk sac tumor (YS) and choriocarcinoma. We have analyzed the genomes and epigenomes of pure histological forms of TGCT (n=130) and 128 matched adjacent normal testicular tissues for TGCT core and subtype-specific DNA methylome profiles and somatic copy number aberrations (SCNA). Original data were compared with published data sets focused on differentiated and pluripotent states. First, we identified pan-TGCT recurrent erasure of maternal and paternal germline imprints and DPPA3 (STELLA), consistent with an embryonic germ cell ancestry. Beyond these conserved properties, we identified TGCT subtype-dependent epigenomic congruency with pluripotent versus somatic reference lineages, thereby establishing competency for lineage-conforming methylation reprogramming in the multi-potent common ancestor of TGCT. Notable subtype programming distinctions are as follows: the SE methylome reflects a ground-state of germ cell erasure; EC is found to harbor pervasive embryonic stem cell (ESC)-like CpH (non-CpG) methylation, absent in other TGCT and non-germ cell tumors and differentiated tissues. EC was further distinguished by ESC-like hypomethylation of NANOG, contrasting with NANOG methylation in TE, YS, and somatic tissues. Thus, EC methylomes present a novel mixed ESC/embryonic germ cell epigenomic state. TE global methylation was most convergent with somatic tissue; however, and unique among TGCT subtypes, TE manifested hypermethylation of the H19 paternal germline DMR. The YS methylome most closely resembled extra-embryonic trophoblast. The total set of findings provides evidence for a multi-potent TGCT stem cell whose progeny may harbor pluripotent, primordial germ/gonocyte, and somatic lineage-defining methylation marks. Despite such competency, no TGCT subtype restored erased parental germline imprints. TE is the exception, with H19 hypermethylation. Benign testis adjacent to TGCT exhibited a bimodal epigenotype distribution determined by spermatogenesis and significantly associated with high versus low Johnsen score. Overall, TGCT methylomes are trapped in a core embryonic germ cell-like state of DPPA3/STELLA and imprint erasure, while differential somatic and pluripotent reprogramming profiles are otherwise established.

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Expression data from cell lines forced expressed PGC7/Stella

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