scholarly journals Active DNA demethylation of developmental cis-regulatory regions predates vertebrate origins

2021 ◽  
Author(s):  
Ksenia Skvortsova ◽  
Stephanie Bertrand ◽  
Danila Voronov ◽  
Paul Edward Duckett ◽  
Samuel E Ross ◽  
...  
Keyword(s):  
Major Gene ◽  
Dna Methyltransferases ◽  
Dna Demethylation ◽  
Regulatory Regions ◽  
Genomic Distribution ◽  
Active Dna Demethylation ◽  
Regulatory Module ◽  
Gene Regulatory ◽  
Tet Enzymes ◽  
Shed Light

DNA methylation (5-methylcytosine; 5mC) is a repressive gene-regulatory mark required for vertebrate embryogenesis. Genomic 5mC is tightly regulated through the coordinated action of DNA methyltransferases, which deposit 5mC, and TET enzymes, which participate in its active removal through the formation of 5-hydroxymethylcytosine (5hmC). TET enzymes are essential for mammalian gastrulation and activation of vertebrate developmental enhancers, however, to date, a clear picture of 5hmC function, abundance, and genomic distribution in non-vertebrate lineages is lacking. By employing base-resolution 5mC and 5hmC quantification during sea urchin and lancelet embryogenesis, we shed light on the roles of non-vertebrate 5hmC and TET enzymes. We find that these invertebrate deuterostomes employ TET enzymes for targeted demethylation of regulatory regions associated with developmental genes and show that the complement of identified 5hmC-regulated genes is conserved to vertebrates. This work thus demonstrates that active 5mC removal from regulatory regions is a common feature of deuterostome embryogenesis suggestive of unexpected deep conservation of a major gene-regulatory module.

scholarly journals RUNX1 induces DNA replication independent active DNA demethylation at SPI1 regulatory regions

2017 ◽  
Vol 18 (1) ◽  
Author(s):  
Shubham Goyal ◽  
Takahiro Suzuki ◽  
Jing-Ru Li ◽  
Shiori Maeda ◽  
Mami Kishima ◽  
...  
Keyword(s):  
Dna Replication ◽  
Dna Demethylation ◽  
Regulatory Regions ◽  
Active Dna Demethylation

scholarly journals Erratum to: RUNX1 induces DNA replication independent active DNA demethylation at SPI1 regulatory regions

2017 ◽  
Vol 18 (1) ◽  
Author(s):  
Shubham Goyal ◽  
Takahiro Suzuki ◽  
Jing‑Ru Li ◽  
Shiori Maeda ◽  
Mami Kishima ◽  
...  
Keyword(s):  
Dna Replication ◽  
Dna Demethylation ◽  
Regulatory Regions ◽  
Active Dna Demethylation

scholarly journals Sustained TNF-α stimulation leads to transcriptional memory that greatly enhances signal sensitivity and robustness

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Zuodong Zhao ◽  
Zhuqiang Zhang ◽  
Jingjing Li ◽  
Qiang Dong ◽  
Jun Xiong ◽  
...  
Keyword(s):  
Endogenous Retrovirus ◽  
Dna Demethylation ◽  
Gene Encoding ◽  
Active Dna Demethylation ◽  
Tnf Α ◽  
Memory Modules ◽  
Signal Sensitivity ◽  
Transcriptional Memory ◽  
Subsequent Activation ◽  
Tet Enzymes

Transcriptional memory allows certain genes to respond to previously experienced signals more robustly. However, whether and how the key proinflammatory cytokine TNF-α mediates transcriptional memory are poorly understood. Using HEK293F cells as a model system, we report that sustained TNF-α stimulation induces transcriptional memory dependent on TET enzymes. The hypomethylated status of transcriptional regulatory regions can be inherited, facilitating NF-κB binding and more robust subsequent activation. A high initial methylation level and CpG density around κB sites are correlated with the functional potential of transcriptional memory modules. Interestingly, the CALCB gene, encoding the proven migraine therapeutic target CGRP, exhibits the best transcriptional memory. A neighboring primate-specific endogenous retrovirus stimulates more rapid, more strong, and at least 100-fold more sensitive CALCB induction in subsequent TNF-α stimulation. Our study reveals that TNF-α-mediated transcriptional memory is governed by active DNA demethylation and greatly sensitizes memory genes to much lower doses of inflammatory cues.

scholarly journals TET Family of Dioxygenases: Crucial Roles and Underlying Mechanisms

2015 ◽  
Vol 146 (3) ◽  
pp. 171-180 ◽  
Author(s):  
Duo Li ◽  
Bin Guo ◽  
Haijing Wu ◽  
Lina Tan ◽  
Qianjin Lu
Keyword(s):  
Gene Expression ◽  
Therapeutic Potential ◽  
Dna Demethylation ◽  
Oxidation Reactions ◽  
Exciting Field ◽  
Tet Proteins ◽  
Active Dna Demethylation ◽  
Health And Disease ◽  
Underlying Mechanisms ◽  
Tet Enzymes

DNA methylation plays an important role in the epigenetic regulation of mammalian gene expression. TET (ten-eleven translocation) proteins, newly discovered demethylases, have sparked great interest since their discovery. TET proteins catalyze 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine in 3 consecutive Fe(II)- and 2-oxoglutarate (2-OG)-dependent oxidation reactions. TET proteins dynamically regulate global or locus-specific 5-methylcytosine and/or 5-hydroxymethylcytosine levels by facilitating active DNA demethylation. In fact, in addition to their role as methylcytosine dioxygenases, TET proteins are closely related to histone modification, interact with metabolic enzymes as well as other proteins, and cooperate in transcriptional regulation. In this review, we summarize the recent progress in this exciting field, highlighting the molecular mechanism by which TET enzymes regulate gene expression and their functions in health and disease. We also discuss the therapeutic potential of targeting TET proteins and aberrant DNA modifications.

scholarly journals Application of 5-Methylcytosine DNA Glycosylase to the Quantitative Analysis of DNA Methylation

2021 ◽  
Vol 22 (3) ◽  
pp. 1072
Author(s):  
Woo Lee Choi ◽  
Young Geun Mok ◽  
Jin Hoe Huh
Keyword(s):  
Dna Methylation ◽  
Strand Break ◽  
Dna Methyltransferases ◽  
Dna Demethylation ◽  
Dna Glycosylase ◽  
Epigenetic Mark ◽  
Gene Expressions ◽  
Independent Manner ◽  
Single Strand Break ◽  
Active Dna Demethylation

In higher eukaryotes DNA methylation is a prominent epigenetic mark important for chromatin structure and gene expression. Thus, profiling DNA methylation is important for predicting gene expressions associated with specific traits or diseases. DNA methylation is achieved by DNA methyltransferases and can be actively removed by specific enzymes in a replication-independent manner. DEMETER (DME) is a bifunctional 5-methylcytosine (5mC) DNA glycosylase responsible for active DNA demethylation that excises 5mC from DNA and cleaves a sugar-phosphate bond generating a single strand break (SSB). In this study, DME was used to analyze DNA methylation levels at specific epialleles accompanied with gain or loss of DNA methylation. DME treatment on genomic DNA generates SSBs in a nonsequence-specific fashion proportional to 5mC density, and thus DNA methylation levels can be easily measured when combined with the quantitative PCR (qPCR) method. The DME-qPCR analysis was applied to measure DNA methylation levels at the FWA gene in late-flowering Arabidopsis mutants and the CNR gene during fruit ripening in tomato. Differentially methylated epialleles were successfully distinguished corresponding to their expression levels and phenotypes. DME-qPCR is proven a simple yet effective method for quantitative DNA methylation analysis, providing advantages over current techniques based on methylation-sensitive restriction digestion.

scholarly journals Epigenetic Regulation of Genomic Stability by Vitamin C

2021 ◽  
Vol 12 ◽  
Author(s):  
John P. Brabson ◽  
Tiffany Leesang ◽  
Sofia Mohammad ◽  
Luisa Cimmino
Keyword(s):  
Dna Methylation ◽  
Vitamin C ◽  
Excision Repair ◽  
Antioxidant Properties ◽  
Genomic Stability ◽  
Dna Demethylation ◽  
Dna Hypermethylation ◽  
Active Dna Demethylation ◽  
Base Excision ◽  
Tet Enzymes

DNA methylation plays an important role in the maintenance of genomic stability. Ten-eleven translocation proteins (TETs) are a family of iron (Fe2+) and α-KG -dependent dioxygenases that regulate DNA methylation levels by oxidizing 5-methylcystosine (5mC) to generate 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). These oxidized methylcytosines promote passive demethylation upon DNA replication, or active DNA demethylation, by triggering base excision repair and replacement of 5fC and 5caC with an unmethylated cytosine. Several studies over the last decade have shown that loss of TET function leads to DNA hypermethylation and increased genomic instability. Vitamin C, a cofactor of TET enzymes, increases 5hmC formation and promotes DNA demethylation, suggesting that this essential vitamin, in addition to its antioxidant properties, can also directly influence genomic stability. This review will highlight the functional role of DNA methylation, TET activity and vitamin C, in the crosstalk between DNA methylation and DNA repair.

scholarly journals Evolution of regulatory networks associated with traits under selection in cichlids

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Tarang K. Mehta ◽  
Christopher Koch ◽  
Will Nash ◽  
Sara A. Knaack ◽  
Padhmanand Sudhakar ◽  
...  
Keyword(s):  
Visual System ◽  
Regulatory Sequence ◽  
Potential Candidate ◽  
East African ◽  
Regulatory Regions ◽  
A Genome ◽  
Opsin Genes ◽  
East African Cichlids ◽  
Gene Regulatory ◽  
African Cichlids

Abstract Background Seminal studies of vertebrate protein evolution speculated that gene regulatory changes can drive anatomical innovations. However, very little is known about gene regulatory network (GRN) evolution associated with phenotypic effect across ecologically diverse species. Here we use a novel approach for comparative GRN analysis in vertebrate species to study GRN evolution in representative species of the most striking examples of adaptive radiations, the East African cichlids. We previously demonstrated how the explosive phenotypic diversification of East African cichlids can be attributed to diverse molecular mechanisms, including accelerated regulatory sequence evolution and gene expression divergence. Results To investigate these mechanisms across species at a genome-wide scale, we develop a novel computational pipeline that predicts regulators for co-extant and ancestral co-expression modules along a phylogeny, and candidate regulatory regions associated with traits under selection in cichlids. As a case study, we apply our approach to a well-studied adaptive trait—the visual system—for which we report striking cases of network rewiring for visual opsin genes, identify discrete regulatory variants, and investigate their association with cichlid visual system evolution. In regulatory regions of visual opsin genes, in vitro assays confirm that transcription factor binding site mutations disrupt regulatory edges across species and segregate according to lake species phylogeny and ecology, suggesting GRN rewiring in radiating cichlids. Conclusions Our approach reveals numerous novel potential candidate regulators and regulatory regions across cichlid genomes, including some novel and some previously reported associations to known adaptive evolutionary traits.

scholarly journals Positioning of nucleosomes containing γ-H2AX precedes active DNA demethylation and transcription initiation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Stephanie Dobersch ◽  
Karla Rubio ◽  
Indrabahadur Singh ◽  
Stefan Günther ◽  
Johannes Graumann ◽  
...  
Keyword(s):  
Transcription Initiation ◽  
High Mobility ◽  
Dna Demethylation ◽  
High Mobility Group ◽  
Regulation Of Transcription ◽  
Dna Breaks ◽  
Transcriptional Initiation ◽  
High Mobility Group Proteins ◽  
Active Dna Demethylation ◽  
Repair Mechanisms

AbstractIn addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group proteins are the most abundant. Chromatin-mediated regulation of transcription involves DNA methylation and histone modifications. However, the order of events and the precise function of high-mobility group proteins during transcription initiation remain unclear. Here we show that high-mobility group AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT complex to incorporate nucleosomes containing the histone variant H2A.X. Further, phosphorylation of H2A.X at S139 (γ-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support the concept that chromatin opening during transcriptional initiation involves intermediates with DNA breaks that subsequently require DNA repair mechanisms to ensure genome integrity.

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