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Whole genome bisulfite sequencing of E13.0 and E13.5 Tex14 mutant, heterozygote and wild-type murine female germ cells

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE165010 | GEO | 2021/04/06

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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Whole genome bisulfite sequencing of E13.0 and E13.5 Tex14 mutant, heterozygote and wild-type murine female germ cells

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