Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA299011 | ENA |
REPOSITORIES: ENA
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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.
2016-09-15 | GSE74104 | GEO
Project description:Meiosis is critical to generating oocytes however, the mechanisms regulating the switch from mitotic primordial germ cells (PGCs) to meiotic germ cells are poorly understood in females. We showed that the onset of meiosis in the fetal murine ovary propagates via intercellular bridges between developing germ cells by using Tex14 mutant (Tex14-/-) mice. Tex14-/- germ cells, which lack intercellular bridges, initiates meiosis prematurely and they more rapidly extinguish pluripotency-associated transcripts (such as Dppa3) upon entering meiosis. Considering the involvement of Dppa3 in methylation process as well as the importance of epigenetic reprogramming for gamete formation and meiosis, we isolated Tex14 wild-type, heterozygous and mutant germ cells from E13.0 and E13.5 ovaries for whole genome bisulfite sequencing. We compared how methylation differs between age-matched wild-type/heterozygous controls and mutants. We find that DNA methylation across the genome is not affected in Tex14 mutant germ cells however, promoters of Germline Reprogramming Responsive (GRR) genes and younger L1 genes are hypomethylated. These results suggest that cytoplasmic sharing via intercellular bridges slows and coordinates the cell state transition from pluripotency to meiosis potentially by diluting regulatory factors of epigenetic reprogramming.
2021-04-06 | GSE165010 | GEO
Project description:Germ cell neoplasia in situ (GCNIS) is the noninvasive precursor of testicular germ cell tumors type II (TGCT), the most common cancer in young men. GCNIS originates from embryonic germ cells blocked in their maturation. The causes are unknown. GCNIS is associated with impaired Sertoli cells that express fetal marker keratin 18 (KRT18) and pluripotency factor SOX2. According to the spread theory of the origin of GCNIS, these impaired Sertoli cells are prepubertal cells arrested in their maturation due to genetic anomalies and/ or environmental anti-androgens. Thus, they are unable to support the development of germ cells, leading to their maturational block with further progression into GCNIS. The alternative theory states that the impaired Sertoli cells are adult cells dedifferentiating secondarily due to the influence of GCNIS. To address this issue, we established a co-culture model of adult human Sertoli cells (FS1) and a seminoma cell line similar to GCNIS (TCam-2). After 2 weeks of co-culture, FS1 cells showed progressive expression of KRT18 and SOX2. Interestingly, TCam-2 cells in co-culture showed SOX2 expression and upregulation of further pluripotency- and reprogramming-associated genes (LEFTY1/2, GAL, DPPA5, NODAL, ZIC3, DND1, DPPA3, GDF3, BCAT1, JARID2, and DNMT3B), suggesting a seminoma to embryonal carcinoma transition. Thus, our FS1/ TCam-2 co-culture model is a valuable tool to investigate interactions between Sertoli cells and tumor cells. Our studies of human testicular biopsies with GCNIS further suggest that the impaired Sertoli cells associated to GCNIS represent adult cells undergoing progressive dedifferentiation.
2022-03-01 | GSE169557 | GEO
Project description:Genome-wide DNA demethylation is a unique feature of mammalian development and naïve pluripotent stem cells. So far, it was unclear how mammals specifically achieve global DNA hypomethylation, given the high conservation of the DNA (de-)methylation machinery among vertebrates. We found that DNA demethylation requires TET activity but mostly occurs at sites where TET proteins are not bound suggesting a rather indirect mechanism. Among the few specific genes bound and activated by TET proteins was the naïve pluripotency and germline marker Dppa3 (Pgc7, Stella), which undergoes TDG dependent demethylation. The requirement of TET proteins for genome-wide DNA demethylation could be bypassed by ectopic expression of Dppa3. We show that DPPA3 binds and displaces UHRF1 from chromatin and thereby prevents the recruitment and activation of the maintenance DNA methyltransferase DNMT1. We demonstrate that DPPA3 alone can drive global DNA demethylation when transferred to amphibians (Xenopus) and fish (medaka), both species that naturally do not have a Dppa3 gene and exhibit no post-fertilization DNA demethylation. Our results show that TET proteins are responsible for active and - indirectly also for - passive DNA demethylation; while TET proteins initiate local and gene-specific demethylation in vertebrates, the recent emergence of DPPA3 introduced a unique means of genome-wide passive demethylation in mammals and contributed to the evolution of epigenetic regulation during early mammalian development.
2020-10-12 | PXD019794 | Pride
Project description:Testicular germ cell tumors are among the most responsive solid cancers to conventional chemotherapy. To elucidate the underlying mechanisms, we developed a mouse testicular germ cell tumor model in which germ cell-specific oncogenic Kras activation and tumor suppressor Pten inactivation was driven by CRE-mediated recombination. The resulting mice rapidly developed malignant, metastatic testicular cancers composed of both teratoma and embryonal carcinoma, the latter of which exhibited stem cell characteristics, including expression of the pluripotency factor OCT4. As part of our analysis of mouse gPAK testicular tumors, as well as comparison to benign 129-Dnd1Ter/Ter testicular teratomas, we used NimbleGen Mouse CGH 3x720k Whole-Genome Tiling Arrays to assess copy number variations in this novel genetically engineered mouse model of malignant, metastatic testicular cancer.
2017-11-14 | GSE70746 | GEO
Project description:Distinct cell types emerge from embryonic stem cells through a precise and coordinated execution of gene expression programs during lineage commitment. This is established by the action of lineage specific transcription factors along with chromatin complexes. Numerous studies focused on epigenetic factors that affect ESC self-renewal and pluripotency. Through our laboratory's previous studies on ESCs pluripotency, we found that Dppa3, as a Naive state marker gene, is of great significance to the transformation of mESCs pluripotency. However, the influence of overexpression of Dppa3 in ESCs on mESCs status has not been determined. Our results show that overexpression of Dppa3 induces global DNA demethylation, which is beneficial to the maintenance of pluripotency, but its differentiation ability is significantly impaired. In mESCs, Dppa3 regulates mESCs pluripotency by inhibiting de novo methylation pathway, maintaining methylation pathway, promoting demethylation pathway Tet2, up-regulating active histone modification and down-regulating heterogeneous histone modification. The 2C-like state of ESCs recapitulates key aspects of the two-cell stage mouse embryo both phenotypically and molecular, which providing a cellular model to investigate the progress of ZGA. Our results found Dppa3 promote facilitate 2C-state conversion.
2022-06-28 | GSE197967 | GEO
Project description:The somatic microenvironment supports spermatogonial stem cell differentiation into sperm. Extracellular matrix (ECM) plays multiple roles in the stem cell niche, including self-renewal, proliferation, differentiation and survival of spermatogonial cells. The pathophysiology of male infertility might be representative of a progressive degenerative process of the testicular tissue, including ECM, rather than a defective genetic background, thus outlining the existence of chronic etiological agents/pathways. In this context, we sought to identify potential causative factors responsible for a number of modifications of the testicular somatic microenvironment associated with idiopathic germ cell aplasia in human beings. Proteomic analysis of the decellularized ECM was performed to study testis parenchyma from 10 idiopathic non-obstructive azoospermic (iNOA) men, dichotomized according to positive sperm retrieval versus germ cell aplasia. Germ cell aplasia was characterized by an increased nuclear distribution of the retinoic acid receptor in Sertoli cells which was associated with decreased expression of the ECM markers, Nidogen-2 and Heparan sulfate proteoglycan-2. Decreased levels of the interstitial matrisome associated Factor IX and its regulator VKORC1 were instead coupled with decreased signaling of vitamin K in Leydig cells. This study identified pathogenetic signature of the somatic testicular microenvironment and provide mechanistic insights into the molecular determinants of human idiopathic germ cell aplasia.
2019-01-07 | PXD011817 | Pride
Project description:In response to signals from the embryonic testis, germ cell intrinsic factor NANOS2 coordinates a sex-specific transcriptional program necessary for differentiation of pluripotent-like primordial germ cells toward a unipotent spermatogonial stem cell fate. Emerging evidence indicates that genetic risk factors contribute to testicular germ cell tumor initiation by disrupting sex-specific differentiation. Here, using a mouse model of spontaneous testicular teratomas, we report that a subpopulation of germ cells failing to express NANOS2 is enriched for developmental phenotypes required for tumorigenesis. We demonstrate that only in the absence of NANOS2 do germ cells have a transcriptional profile enriched for Myc signaling and primed pluripotency and transform into embryonal carcinoma cells. We conclude that NANOS2 is the nexus through which many genetic risk factors exert their influence on tumor susceptibility. We propose that NODAL signaling, which is present in the developing testis, drives germ cell transformation in the absence of sex specification.
2020-09-03 | GSE157362 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE35775: The H3K27 demethylase Utx facilitates somatic and germ cell epigenetic reprogramming to pluripotency [Affymetrix gene expression] GSE37821: The H3K27 demethylase Utx facilitates somatic and germ cell epigenetic reprogramming to pluripotency [ChIP-Seq] Refer to individual Series
2012-05-29 | E-GEOD-37822 | biostudies-arrayexpress
Project description:Recognized molecular similarities between pluripotency and cancer have recently been underscored with multi-omics campaigns revealing stemness networks that are shared between human pluripotent stem cells (hPSCs) and tumors, where tumors types cluster based on tissue origins. Informed by these in silico studies, we now demonstrate hPSCs serve as a source of networks that define properties of adult tissue oncogenesis. Single cell deconstruction of hPSCs allowed germ layer primed subsets to be identified that corresponded to lineage specified adult cancers. Chemical probes that induced germ layer differentiation of hPSCs also suppressed adult cancers, but were restricted to tumors of shared origin with germ layer specification. Metallothioneines induced mesoderm differentiation of hPSC with exclusive ability to overcome differentiation block of human leukemia. Our study provides causal evidence for a relationship between pluripotent state and human cancer that defines oncogenic reprogramming and thereby identify covert targets for cancer therapy.
2023-05-17 | GSE133041 | GEO