DNA methylation and the core pluripotency network

Shanak, Siba$AAUP$Palestinian; Helms, Volkhard$Other$Other

doi:10.1016/j.ydbio.2020.06.001

Cited by 21 publications

(14 citation statements)

References 237 publications

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“…A clear difference in the DNA methylation levels in regions within pluripotent and developmental genes was noted between the two fibroblast lines, suggesting that even a 50% reduction in the levels of two pluripotent genes is sufficient to induce aberrant DNA methylation during development. In fact, although Oct4 expression level was not affected in the iPSCs, GEO enrichment of the derived MEFs showed loss of function of Oct4 as a core pluripotency player which can be explained by the fact that key pluripotent genes such as Nanog , Sox2 , Sall4 and Esrrb who have been shown to regulate and function with the core DNA methylation machinery were missing (Adachi et al, 2018; Shanak and Helms, 2020; Tan et al, 2013).…”

Section: Discussionmentioning

confidence: 97%

Fibroblasts-derived from Pluripotent Cells Harboring a Single Allele Knockout in Two Pluripotency Genes Exhibit DNA Methylation Abnormalities and pluripotency induction Defects

Lasry¹,

Maoz²,

Cheng

et al. 2022

Preprint

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A complete knockout (KO) of a single key pluripotency gene has been shown to drastically affect embryonic stem cell (ESC) function and epigenetic reprogramming. However, knockin (KI)/KO of a reporter gene only in one of two alleles in a single pluripotency gene is considered harmless and is largely used in the stem cell field. Here, we sought to understand the impact of simultaneous elimination of a single allele in two ESC key genes on pluripotency potential and acquisition. We established multiple pluripotency systems harboring KI/KO in a single allele of two different pluripotency genes (i.e. Nanog+/-; Sall4+/-, Nanog+/-; Utf1+/-, Nanog+/-; Esrrb+/- and Sox2+/-; Sall4+/-). Interestingly, although these double heterozygous mutant lines maintain their stemness and contribute to chimeras equally to their parental control cells, fibroblasts derived from these systems show a significant reduction in their capability to induce pluripotency either by Oct4, Sox2, Klf4 and Myc (OSKM) or by nuclear transfer (NT). Tracing the expression of Sall4 and Nanog, as representative key pluripotency targeted genes, at early phases of reprogramming could not explain the seen delay/blockage. Further exploration identifies abnormal methylation landscape around pluripotent and developmental genes in the double heterozygous mutant fibroblasts. Accordingly, treatment with 5-azacytidine two days prior to transgene induction rescues the reprogramming defects. This study emphasizes the importance of maintaining two intact alleles for pluripotency induction and suggests that insufficient levels of key pluripotency genes leads to DNA methylation abnormalities in the derived-somatic cells later on in development.

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Section: Discussionmentioning

confidence: 97%

Fibroblasts-derived from Pluripotent Cells Harboring a Single Allele Knockout in Two Pluripotency Genes Exhibit DNA Methylation Abnormalities and pluripotency induction Defects

Lasry¹,

Maoz²,

Cheng

et al. 2022

Preprint

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“…Intriguingly, EcPou5f1 was not detected in those nongonadal tissues expressing the short DNA fragment or protein of EcNanog . We guess that other regulators, such as Sox2 and Klf4, and the auto-regulatory of Nanog might account for the absence of EcPou5f1 in nongonadal tissues [ 46 , 47 ]. In short, the tissue distributions of Pou5f1 and Nanog show species differences to a variable extent in diverse fish, and suggest that they play multifunctional roles in gonads and somatic tissues.…”

Section: Discussionmentioning

confidence: 99%

Pou5f1 and Nanog Are Reliable Germ Cell-Specific Genes in Gonad of a Protogynous Hermaphroditic Fish, Orange-Spotted Grouper (Epinephelus coioides)

Zhong

Liu

Tao

et al. 2021

Genes

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Pluripotency markers Pou5f1 and Nanog are core transcription factors regulating early embryonic development and maintaining the pluripotency and self-renewal of stem cells. Pou5f1 and Nanog also play important roles in germ cell development and gametogenesis. In this study, Pou5f1 (EcPou5f1) and Nanog (EcNanog) were cloned from orange-spotted grouper, Epinephelus coioides. The full-length cDNAs of EcPou5f1 and EcNanog were 2790 and 1820 bp, and encoded 475 and 432 amino acids, respectively. EcPou5f1 exhibited a specific expression in gonads, whereas EcNanog was expressed highly in gonads and weakly in some somatic tissues. In situ hybridization analyses showed that the mRNA signals of EcNanog and EcPou5f1 were exclusively restricted to germ cells in gonads. Likewise, immunohistofluorescence staining revealed that EcNanog protein was limited to germ cells. Moreover, both EcPou5f1 and EcNanog mRNAs were discovered to be co-localized with Vasa mRNA, a well-known germ cell maker, in male and female germ cells. These results implied that EcPou5f1 and EcNanog could be also regarded as reliable germ cell marker genes. Therefore, the findings of this study would pave the way for elucidating the mechanism whereby EcPou5f1 and EcNanog regulate germ cell development and gametogenesis in grouper fish, and even in other protogynous hermaphroditic species.

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“…It has been suggested that changes in intragenic DNA methylation is important in several human diseases including syndromic and sporadic forms of various neurological disorders that involve methylation defects, including Rett syndrome, Prader–Willi and Angelman syndromes, and others, suggesting that the differential (de)methylation of genes may underpin one aspect of various neurological disorders ( Dunaway et al, 2016 ; Rogozin et al, 2018a ; Scandaglia and Barco, 2019 ). Such differential methylation may be caused by differences in (de)methylation processes in somatic/germ cells ( Shanak and Helms, 2020 ). Moreover, several studies of likely deleterious mutations have observed that genes controlling methylation status, chromatin accessibility or remodeling (and hence gene expression) are enriched for genes with recurrent mutations ( Geschwind and State, 2015 ; Sanders et al, 2015 ; Geisheker et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation, Deamination, and Translesion Synthesis Combine to Generate Footprint Mutations in Cancer Driver Genes in B-Cell Derived Lymphomas and Other Cancers

et al. 2021

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Cancer genomes harbor numerous genomic alterations and many cancers accumulate thousands of nucleotide sequence variations. A prominent fraction of these mutations arises as a consequence of the off-target activity of DNA/RNA editing cytosine deaminases followed by the replication/repair of edited sites by DNA polymerases (pol), as deduced from the analysis of the DNA sequence context of mutations in different tumor tissues. We have used the weight matrix (sequence profile) approach to analyze mutagenesis due to Activation Induced Deaminase (AID) and two error-prone DNA polymerases. Control experiments using shuffled weight matrices and somatic mutations in immunoglobulin genes confirmed the power of this method. Analysis of somatic mutations in various cancers suggested that AID and DNA polymerases η and θ contribute to mutagenesis in contexts that almost universally correlate with the context of mutations in A:T and G:C sites during the affinity maturation of immunoglobulin genes. Previously, we demonstrated that AID contributes to mutagenesis in (de)methylated genomic DNA in various cancers. Our current analysis of methylation data from malignant lymphomas suggests that driver genes are subject to different (de)methylation processes than non-driver genes and, in addition to AID, the activity of pols η and θ contributes to the establishment of methylation-dependent mutation profiles. This may reflect the functional importance of interplay between mutagenesis in cancer and (de)methylation processes in different groups of genes. The resulting changes in CpG methylation levels and chromatin modifications are likely to cause changes in the expression levels of driver genes that may affect cancer initiation and/or progression.

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DNA methylation and the core pluripotency network

Cited by 21 publications

References 237 publications

Fibroblasts-derived from Pluripotent Cells Harboring a Single Allele Knockout in Two Pluripotency Genes Exhibit DNA Methylation Abnormalities and pluripotency induction Defects

Fibroblasts-derived from Pluripotent Cells Harboring a Single Allele Knockout in Two Pluripotency Genes Exhibit DNA Methylation Abnormalities and pluripotency induction Defects

Pou5f1 and Nanog Are Reliable Germ Cell-Specific Genes in Gonad of a Protogynous Hermaphroditic Fish, Orange-Spotted Grouper (Epinephelus coioides)

DNA Methylation, Deamination, and Translesion Synthesis Combine to Generate Footprint Mutations in Cancer Driver Genes in B-Cell Derived Lymphomas and Other Cancers

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