Identification, Characterization, and Heritability of Murine Metastable Epialleles: Implications for Non-genetic Inheritance

Kazachenka, Anastasiya; Bertozzi, Tessa M.; Sjoberg-Herrera, Marcela K.; Walker, Nicolas; Gardner, Joseph; Gunning, Richard; Pahita, Eleni; Adams, Sarah; Adams, David J.; Ferguson-Smith, Anne C.

doi:10.1016/j.cell.2018.11.017

Cited by 55 publications

(62 citation statements)

References 1 publication

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“…About 100 of them have been identified recently as being variably methylated in C57BL/6 mice, they might, therefore, be involved in epigenetic regulation of gene expression, similar to agouti and axin fused. 124,125 In germline cells, epigenetic marks are normally erased and remodeled in a process termed epigenetic reprogramming. 120 Therefore, epigenetic changes are mostly transient and only affect one individual in its lifetime.…”

Section: Epigenetics and Paramutationsmentioning

confidence: 99%

“…126 For example, the epigenetic marks regulating agouti, axin fused, and a third locus have been shown to be transgenerationally inheritable. 121,123,124 Epigenetic inheritance not directly mediated by DNA modifications but by small RNAs, termed paramutations, is presumably more stable over time. 127 Small RNAmediated paramutations (see below) can last for at least 20 generations in the nematode C. elegans.…”

Section: Epigenetics and Paramutationsmentioning

confidence: 99%

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What viruses tell us about evolution and immunity: beyond Darwin?

Broecker

Moelling

2019

Annals of the New York Academy of Sciences

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We describe mechanisms of genetic innovation mediated by viruses and related elements that, during evolution, caused major genetic changes beyond what was anticipated by Charles Darwin. Viruses and related elements introduced genetic information and have shaped the genomes and immune systems of all cellular life forms. None of these mechanisms contradict Darwin's theory of evolution but extend it by means of sequence information that has recently become available. Not only do small increments of genetic information contribute to evolution, but also do major events such as infection by viruses or bacteria, which can supply new genetic information to a host by horizontal gene transfer. Thereby, viruses and virus‐like elements act as major drivers of evolution.

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Section: Epigenetics and Paramutationsmentioning

confidence: 99%

Section: Epigenetics and Paramutationsmentioning

confidence: 99%

What viruses tell us about evolution and immunity: beyond Darwin?

Broecker

Moelling

2019

Annals of the New York Academy of Sciences

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“…In this study to add insight to the potential functionality of novel ORFs, we take a proteogenomics approach combining total RNA sequencing data of naive B and T cells (GEO94671 [12] from the Blueprint consortium with in-house generated proteomics data from a similar experimental design. We perform comprehensive and systematic analyses of this data to identify novel ORFs in the naive B and T cells from inbred mice that have not been exposed to antigens.…”

Section: Fig 1b Right Panel Demonstrates That the Distribution Of Mmentioning

confidence: 99%

Translational products encoded by novel ORFs may form protein-like structures and have biological functions

Erady

Chong

Meena

et al. 2019

Preprint

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Translation products encoded by non canonical or novel open reading frame (ORF) genomic regions are generally considered too small to play any significant biological role, and dismissed as inconsequential. In this study, we show that mutations mapping to novel ORFs have significantly higher pathogenicity scores than mutations in protein-coding regions. Importantly, novel ORFs can translate into protein-like structures with putative independent biological functions that can be of relevance in disease states, including cancer. We thus provide strong evidence to support the systematic study of novel ORFs to gain new insights into normal biological and disease processes. One Sentence Summary:Non coding regions may encode protein-like products that are important to understand diseases.

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“…Certain IAPs with variable DNA methylation across individuals but persistent methylation across tissues of an individual are known as Variably Methylated IAPs (VM-IAPs) [1]. In order to assess the role of TF binding and de-methylation resistance in the formation of VM-IAPs, we compared the average CpG methylation in E13.5m PGCs and the affinity of putative reprogramming and non-reprogramming TFs expressed in E16.5m PGCs at VM vs non-VM IAPs of the same class, for the 3 classes of IAPs with at least 25 validated VM-IAPs ( Figure 6C).…”

Section: Iaps Possess a Relatively Low Affinity For Embryonic Reprogrmentioning

confidence: 99%

“…Evidence for the transmission of phenotypic traits via inter-and trans-generational epigenetic inheritance in mammals has grown substantially in recent years. However, the underlying mechanisms responsible for these phenomena have remained elusive [1,2]. DNA methylation is arguably the best candidate carrier of epigenetic information and an appealing option to explain inter-and trans-generational epigenetic inheritance, since it is heritable across rounds of DNA replication.…”

Section: Introductionmentioning

confidence: 99%

Transcription factors protect from DNA re-methylation during reprograming of primordial germ cells and pre-implantation embryos

Kremsky

Corcés

2019

Preprint

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A growing body of evidence suggests that certain phenotypic traits of epigenetic origin can be passed across generations via both the male and female germlines of mammals. These observations have been difficult to explain owing to a global loss of the majority of known epigenetic marks present in parental chromosomes during primordial germ cell development and after fertilization. By integrating previously published BS-seq, DNase-seq, ATAC-seq, and RNA-seq data collected during multiple stages of primordial germ cell and preimplantation development, we find that the methylation status of the majority of CpGs genome-wide is restored after global reprogramming, despite the fact that global CpG methylation drops to 10% in primordial germ cells and 20% in the inner cell mass of the blastocyst. We estimate the proportion of such CpGs with preserved methylation status to be 78%. Further, we find that CpGs at sites bound by transcription factors during the global re-methylation phases of germ line and embryonic development remain hypomethylated across all developmental stages observed. On the other hand, CpGs at sites not bound by transcription factors during the global re-methylation phase have high methylation levels prior to global de-methylation, become demethylated during global de-methylation, and then become re-methylated. The results suggest that transcription factors can act as carriers of epigenetic information during germ cell and preimplantation development by ensuring that the methylation status of CpGs is maintained after reprogramming of DNA methylation. Based on our findings, we propose a model in which transcription factor binding during the re-methylation phases of primordial germ cell and preimplantation development allow epigenetic information to be maintained trans-generationally even at sites where DNA methylation is lost during global de-methylation.

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Identification, Characterization, and Heritability of Murine Metastable Epialleles: Implications for Non-genetic Inheritance

Cited by 55 publications

References 1 publication

What viruses tell us about evolution and immunity: beyond Darwin?

What viruses tell us about evolution and immunity: beyond Darwin?

Translational products encoded by novel ORFs may form protein-like structures and have biological functions

Transcription factors protect from DNA re-methylation during reprograming of primordial germ cells and pre-implantation embryos

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