Mother–child transmission of epigenetic information by tunable polymorphic imprinting

Carpenter, Brittany L.; Zhou, Wanding; Madaj, Zachary; DeWitt, Ashley K.; Ross, Jason P.; Grønbæk, Kirsten; Liang, Gangning; Clark, Susan J.; Molloy, Peter L.; Jones, Peter A.

doi:10.1073/pnas.1815005115

Cited by 39 publications

(119 citation statements)

References 69 publications

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“…This latter observation aligns with a growing body of evidence linking early environment, notably nutritional factors involved in one-carbon (C1) metabolism with methylation at imprinted regions 20,21 . Indeed we have previously noted an association between season of conception and several C1 metabolites at a maternally imprinted region at the small non-coding RNA VTRNA2-1 22 , consistent with evidence of 'polymorphic imprinting' linked to prenatal environment at this locus 23,37 . Furthermore, we previously found strong enrichment for proximal binding sites of several transcription factors (TFs) associated with the maintenance of PofOm in the early embryo at MEs 18 , although we were unable to replicate this at SoC-associated loci identified in this study.…”

Section: Discussionsupporting

confidence: 81%

Environmentally sensitive hotspots in the methylome of the early human embryo

Silver

Saffari

Kessler

et al. 2019

Preprint

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In humans, DNA methylation marks inherited from sperm and egg are largely erased immediately following conception, prior to construction of the embryonic methylome. Exploiting a natural experiment of cyclical seasonal variation including changes in diet and nutritional status in rural Gambia, we replicated 134 loci with a common season-ofconception methylation signature in two independent child cohorts. These robust candidates for sensitivity to early environment were highly enriched for metastable epialleles, parent-of-origin specific methylation and regions hypomethylated in sperm. They tended to co-locate with endogenous retroviral (ERV1, ERVK) elements. Identified loci were influenced but not determined by measured genetic variation, notably through geneenvironment interactions. To the extent that early methylation changes impact gene expression, environmental sensitivity during genomic remethylation in the very early embryo could thus constitute a sense-record-adapt mechanism linking early environment to later phenotype. RESULTS Association of DNA methylation with Gambian season of conception

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Section: Discussionsupporting

confidence: 81%

Environmentally sensitive hotspots in the methylome of the early human embryo

Silver

Saffari

Kessler

et al. 2019

Preprint

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“…nc886 has a strong CpG island at the promoter region and its expression is silenced in a subset of malignant cells by DNA hypermethylation at the CpG island (Park et al, ). nc886 silencing occurs frequently in a number of malignancies (Ahn et al, ; Cao et al, ; Fort et al, ; Lee, Lee, et al, ; Lee, Park, et al, ; Park et al, ; Treppendahl et al, ), presumably because nc886 is an imprinted gene (Carpenter et al, ; Paliwal et al, ; Romanelli et al, ). Unlike typical imprinted genes which show monoallelic methylation in 100% of individuals, nc886 is estimated to be methylated in the maternal allele in approximately 75% of individuals (Treppendahl et al, ).…”

Section: Cellular Rnas That Controls Pkrmentioning

confidence: 99%

“…As aforementioned, nc886 has a CpG island at its promoter region, whose hypermethylation results in nc886 silencing. Because nc886 is an imprinted gene (Carpenter et al, ; Paliwal et al, ; Romanelli et al, ), nc886 silencing occurs frequently in cancer. Together with nc886's high affinity to PKR (Jeon, Lee, et al, ), the complete silencing of nc886 from its normally abundant expression level (Lee et al, ) is expected to activate PKR robustly.…”

Section: Pkr Regulation In Cancermentioning

confidence: 99%

“…CTCF is known to be an insulator for chromatin structure, which prevents spreading of epigenetic features from one chromatin domain to another (Ong & Corces, 2014). More importantly, nc886 methylation of offsprings is influenced by nutrient status during mother's periconceptional period (Silver et al, 2015) and age at delivery (Carpenter et al, 2018). This is a fascinating example how maternal environments affect the epigenotype of offsprings.…”

Section: Nc886mentioning

confidence: 99%

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Protein kinase R and its cellular regulators in cancer: An active player or a surveillant?

2019

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Protein kinase R (PKR), originally known as an antiviral protein, senses various stresses as well as pathogen‐driven double‐stranded RNAs. Thereby activated PKR provokes diverse downstream events, including eIF2α phosphorylation and nuclear factor kappa‐light‐chain‐enhancer of activated B cells activation. Consequently, PKR induces apoptosis and inflammation, both of which are highly important in cancer as much as its original antiviral role. Therefore, cellular proteins and RNAs should tightly control PKR activity. PKR and its regulators are often dysregulated in cancer and it is undoubted that such dysregulation contributes to tumorigenesis. However, PKR's precise role in cancer is still in debate, due to incomprehensible and even contradictory data. In this review, we introduce important cellular PKR regulators and discuss about their roles in cancer. Among them, we pay particular attention to nc886, a PKR repressor noncoding RNA that has been identified relatively recently, because its expression pattern in cancer can explain interesting yet obscure oncologic aspects of PKR. Based on nc886 and its regulation of PKR, we have proposed a tumor surveillance model, which reconciles contradictory data about PKR in cancer. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

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“…In agreement with their higher chromatin correlation, the vtRNA1 cluster have a larger core of common TFs (39) in comparison with vtRNA2-1 (23 TFs). The divergence of the transcriptional control of vtRNA2-1 was previously recognized given its unique regulatory elements and the complex developmental methylation it undergoes (Canella et al, 2010;Carpenter et al, 2018;Helbo et al, 2017;Nandy et al, 2009). Remarkably, the 23 TFs common to all vtRNAs are related to viral infections and cancer.…”

Section: Discussionmentioning

confidence: 99%

Pan-Cancer chromatin analysis of the human vtRNA genes uncovers their association with cancer biology

Fort

Duhagon

2020

Preprint

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The vault RNAs (vtRNAs) are a class of 84-141 nt eukaryotic non-coding RNAs transcribed by RNA polymerase III, named for their association with the conserved vault particle, a riboprotein complex whose function remains poorly understood. Of the 4 human vtRNA genes, the three clustered at locus 1, i.e. vtRNA1-1, vtRNA1-2 and vtRNA1-3, are integral components of the vault particle, while vtRNA2-1 is a more divergent homologue located in a second locus. Gene expression studies of vtRNAs in large cancer cohorts have been hindered by the failure of vtRNA sequencing using conventional transcriptomic approaches. However, since the vtRNAs transcription is regulated by DNA methylation, the analysis of the chromatin status of their promoters is a suitable surrogate approach to study their expression. Here we infer the landscape of vtRNA expression in cancer from the genome-wide DNA methylation (Illumina Infinium Human Methylation 450 K BeadChip) and chromatin accessibility (ATAC-seq) data of The Cancer Genome Atlas (TCGA). On average, vtRNA1-1 has the most accessible chromatin, followed by vtRNA1-2, vtRNA2-1 and vtRNA1-3. The correlation of the chromatin status of the vtRNA promoters and the binding sites of a common core of transcription factors stands for their transcriptional co-regulation by factors related to viral infection. Yet, vtRNA2-1 is the most independently regulated vtRNA homologue across tissue types. VtRNA1-1 and vtRNA1-3 chromatin status does not significantly change in cancer, though vtRNA1-3 promoter has repressive chromatin marks in a few cancer types. However, vtRNA2-1 and vtRNA1-2 expression are widely deregulated in neoplastic tissues and is compatible with a broad oncogenic role of vtRNA1-2, and both tumor suppressor and oncogenic functions of vtRNA2-1 depending of tissue contexts. Yet, vtRNA1-1, vtRNA1-2 and vtRNA2-1 promoter DNA methylation predicts a shorter patient overall survival cancer-wide. In addition, gene ontology analyses of co-regulated genes identifies a chromosome 5 regulatory domain controlling vtRNA1-1 and neighboring genes, and epithelial differentiation, immune and thyroid cancer gene sets for vtRNA1-2, vtRNA2-1 and vtRNA1-3 respectively. Furthermore, vtRNA expression patterns are associated with cancer immune subtypes. Finally, vtRNA1-2 expression is positively associated with cell proliferation and wound healing, in agreement with its oncogenic expression profile. Overall, our study presents the landscape of vtRNA expression cancer-wide, identifying co-regulated gene networks and ontological pathways associated with the different vtRNA genes that may account for their diverse roles in cancer.

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Mother–child transmission of epigenetic information by tunable polymorphic imprinting

Cited by 39 publications

References 69 publications

Environmentally sensitive hotspots in the methylome of the early human embryo

Environmentally sensitive hotspots in the methylome of the early human embryo

Protein kinase R and its cellular regulators in cancer: An active player or a surveillant?

Pan-Cancer chromatin analysis of the human vtRNA genes uncovers their association with cancer biology

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