Imprints and DPPA3 are bypassed during pluripotency- and differentiation-coupled methylation reprogramming in
J Keith Killian1, Lambert C J Dorssers2, Britton Trabert3
1Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Abstract:
Testicular germ cell tumors (TGCTs) share germline ancestry but diverge phenotypically and clinically as seminoma (SE) and nonseminoma (NSE), the latter including the pluripotent embryonal carcinoma (EC) and its differentiated derivatives, teratoma (TE), yolk sac tumor (YST), and choriocarcinoma. Epigenomes from TGCTs may illuminate reprogramming in both normal development and testicular tumorigenesis. Herein we investigate pure-histological forms of 130 TGCTs for conserved and subtype-specific DNA methylation, including analysis of relatedness to pluripotent stem cell (ESC, iPSC), primordial germ cell (PGC), and differentiated somatic references. Most generally, TGCTs conserve PGC-lineage erasure of maternal and paternal genomic imprints and DPPA3 (also known as STELLA); however, like ESCs, TGCTs show focal recurrent imprinted domain hypermethylation. In this setting of shared physiologic erasure, NSEs harbor a malignancy-associated hypermethylation core, akin to that of a diverse cancer compendium. Beyond these concordances, we found subtype epigenetic homology with pluripotent versus differentiated states. ECs demonstrate a striking convergence of both CpG and CpH (non-CpG) methylation with pluripotent states; the pluripotential methyl-CpH signature crosses species boundaries and is distinct from neuronal methyl-CpH. EC differentiation to TE and YST entails reprogramming toward the somatic state, with loss of methyl-CpH but de novo methylation of pluripotency loci such as NANOG Extreme methyl-depletion among SE reflects the PGC methylation nadir. Adjacent to TGCTs, benign testis methylation profiles are determined by spermatogenetic proficiency measured by Johnsen score. In sum, TGCTs share collective entrapment in a PGC-like state of genomic-imprint and DPPA3 erasure, recurrent hypermethylation of cancer-associated targets, and subtype-dependent pluripotent, germline, or somatic methylation.
Insights
Testicular germ cell tumors (TGCTs) show epigenetic similarities to primordial germ cells (PGCs) and pluripotent stem cells (PSCs). Different TGCT subtypes exhibit distinct DNA methylation patterns reflecting their developmental state.
Area of Science:
- Oncology
- Epigenetics
- Developmental Biology
Background:
- Testicular germ cell tumors (TGCTs) are classified into seminoma (SE) and nonseminoma (NSE) subtypes, with distinct clinical and phenotypic characteristics.
- Understanding the epigenetic landscape of TGCTs can provide insights into normal development and tumorigenesis.
- Previous studies have explored DNA methylation in TGCTs, but a comprehensive analysis across pure histological subtypes and in relation to developmental states was lacking.
Purpose of the Study:
- To investigate conserved and subtype-specific DNA methylation patterns in pure histological forms of TGCTs.
- To compare the epigenomes of TGCTs with those of pluripotent stem cells (ESCs, iPSCs), primordial germ cells (PGCs), and differentiated somatic cells.
- To elucidate the epigenetic relationship between TGCT subtypes and different developmental stages.
Main Methods:
- Analysis of DNA methylation profiles from 130 pure-histological TGCT samples.
- Comparison of TGCT epigenomes with reference methylomes from ESCs, iPSCs, PGCs, and somatic cells.
- Investigation of both CpG and CpH (non-CpG) methylation patterns.
Main Results:
- All TGCTs exhibit erasure of maternal and paternal genomic imprints and DPPA3, similar to PGCs.
- Nonseminomas (NSEs) display a core malignancy-associated hypermethylation signature distinct from seminomas (SEs).
- Embryonal carcinomas (ECs) show convergence with pluripotent stem cells, particularly in CpH methylation, while teratomas (TEs) and yolk sac tumors (YSTs) reprogram towards a somatic methylation state.
- Seminomas (SEs) exhibit extreme methyl-depletion, reflecting the PGC methylation nadir.
Conclusions:
- TGCTs are epigenetically characterized by a shared PGC-like state of imprint erasure and DPPA3 loss, alongside recurrent hypermethylation in cancer-associated targets.
- Epigenetic profiles of TGCT subtypes correlate with their differentiation status, showing homology to pluripotent or somatic cells.
- These findings highlight the role of epigenetic reprogramming in testicular tumorigenesis and offer potential biomarkers for TGCT subtypes.
More Related Videos
07:08Author Spotlight: Reprogramming Cancer Cells to iPSCs to Study Disease Progression and Treatment Targets
Published on: February 2, 2024
08:01A Two-Step Strategy that Combines Epigenetic Modification and Biomechanical Cues to Generate Mammalian Pluripotent Cells
Published on: August 29, 2020
Related Concept Videos
01:29Somatic to iPS Cell Reprogramming
01:24Methods of Nuclear Reprogramming
01:32Chromatin Modification in iPS Cells
Compact chromatin makes reprogramming difficult. Enzymes, such as histone demethylases and acetyltransferases, are often added during reprogramming to loosen the chromatin, making the DNA more accessible to transcription factors. Molecules that inhibit histone...
02:23Abnormal Proliferation
02:30Genomic Imprinting and Inheritance
The expression of some genes depends on which parent passed the gene to the offspring, through a phenomenon known as...
01:46Epigenetic Regulation