scholarly journals Active DNA Demethylation in Plants

2019 ◽  
Vol 20 (19) ◽  
pp. 4683 ◽  
Author(s):  
Jara Teresa Parrilla-Doblas ◽  
Teresa Roldán-Arjona ◽  
Rafael R. Ariza ◽  
Dolores Córdoba-Cañero
Keyword(s):  
Dna Methylation ◽  
Transcriptional Activation ◽  
Excision Repair ◽  
Epigenetic Modification ◽  
Dna Demethylation ◽  
Plant Responses ◽  
Dna Glycosylases ◽  
Active Dna Demethylation ◽  
Physiological Processes ◽  
Base Excision

Methylation of cytosine (5-meC) is a critical epigenetic modification in many eukaryotes, and genomic DNA methylation landscapes are dynamically regulated by opposed methylation and demethylation processes. Plants are unique in possessing a mechanism for active DNA demethylation involving DNA glycosylases that excise 5-meC and initiate its replacement with unmodified C through a base excision repair (BER) pathway. Plant BER-mediated DNA demethylation is a complex process involving numerous proteins, as well as additional regulatory factors that avoid accumulation of potentially harmful intermediates and coordinate demethylation and methylation to maintain balanced yet flexible DNA methylation patterns. Active DNA demethylation counteracts excessive methylation at transposable elements (TEs), mainly in euchromatic regions, and one of its major functions is to avoid methylation spreading to nearby genes. It is also involved in transcriptional activation of TEs and TE-derived sequences in companion cells of male and female gametophytes, which reinforces transposon silencing in gametes and also contributes to gene imprinting in the endosperm. Plant 5-meC DNA glycosylases are additionally involved in many other physiological processes, including seed development and germination, fruit ripening, and plant responses to a variety of biotic and abiotic environmental stimuli.

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 Thymine DNA Glycosylase Can Rapidly Excise 5-Formylcytosine and 5-Carboxylcytosine

2011 ◽  
Vol 286 (41) ◽  
pp. 35334-35338 ◽  
Author(s):  
Atanu Maiti ◽  
Alexander C. Drohat
Keyword(s):  
Embryonic Development ◽  
Catalytic Mechanism ◽  
Excision Repair ◽  
Dna Demethylation ◽  
Oxidation Products ◽  
Dna Glycosylase ◽  
Thymine Dna Glycosylase ◽  
Active Demethylation ◽  
Active Dna Demethylation ◽  
Base Excision

Thymine DNA glycosylase (TDG) excises T from G·T mispairs and is thought to initiate base excision repair (BER) of deaminated 5-methylcytosine (mC). Recent studies show that TDG, including its glycosylase activity, is essential for active DNA demethylation and embryonic development. These and other findings suggest that active demethylation could involve mC deamination by a deaminase, giving a G·T mispair followed by TDG-initiated BER. An alternative proposal is that demethylation could involve iterative oxidation of mC to 5-hydroxymethylcytosine (hmC) and then to 5-formylcytosine (fC) and 5-carboxylcytosine (caC), mediated by a Tet (ten eleven translocation) enzyme, with conversion of caC to C by a putative decarboxylase. Our previous studies suggest that TDG could excise fC and caC from DNA, which could provide another potential demethylation mechanism. We show here that TDG rapidly removes fC, with higher activity than for G·T mispairs, and has substantial caC excision activity, yet it cannot remove hmC. TDG excision of fC and caC, oxidation products of mC, is consistent with its strong specificity for excising bases from a CpG context. Our findings reveal a remarkable new aspect of specificity for TDG, inform its catalytic mechanism, and suggest that TDG could protect against fC-induced mutagenesis. The results also suggest a new potential mechanism for active DNA demethylation, involving TDG excision of Tet-produced fC (or caC) and subsequent BER. Such a mechanism obviates the need for a decarboxylase and is consistent with findings that TDG glycosylase activity is essential for active demethylation and embryonic development, as are mechanisms involving TDG excision of deaminated mC or hmC.

scholarly journals Tet1 and Tet2 Protect DNA Methylation Canyons against Hypermethylation

2015 ◽  
Vol 36 (3) ◽  
pp. 452-461 ◽  
Author(s):  
Laura Wiehle ◽  
Günter Raddatz ◽  
Tanja Musch ◽  
Meelad M. Dawlaty ◽  
Rudolf Jaenisch ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Fate ◽  
Epigenetic Modification ◽  
Regulation Of Gene Expression ◽  
Mechanistic Explanation ◽  
Dna Demethylation ◽  
Double Knockout ◽  
Developmental Defects ◽  
Active Dna Demethylation ◽  
Underlying Mechanisms

DNA methylation is a dynamic epigenetic modification with an important role in cell fate specification and reprogramming. The Ten eleven translocation (Tet) family of enzymes converts 5-methylcytosine to 5-hydroxymethylcytosine, which promotes passive DNA demethylation and functions as an intermediate in an active DNA demethylation process. Tet1/Tet2 double-knockout mice are characterized by developmental defects and epigenetic instability, suggesting a requirement for Tet-mediated DNA demethylation for the proper regulation of gene expression during differentiation. Here, we used whole-genome bisulfite and transcriptome sequencing to characterize the underlying mechanisms. Our results uncover the hypermethylation of DNA methylation canyons as the genomic key feature of Tet1/Tet2 double-knockout mouse embryonic fibroblasts. Canyon hypermethylation coincided with disturbed regulation of associated genes, suggesting a mechanistic explanation for the observed Tet-dependent differentiation defects. Based on these results, we propose an important regulatory role of Tet-dependent DNA demethylation for the maintenance of DNA methylation canyons, which prevents invasive DNA methylation and allows functional regulation of canyon-associated genes.

scholarly journals TET2-interacting long noncoding RNA promotes active DNA demethylation of the MMP-9 promoter in diabetic wound healing

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Liyan Zhou ◽  
Meng Ren ◽  
Tingting Zeng ◽  
Wei Wang ◽  
Xiaoyi Wang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Excision Repair ◽  
Skin Wound ◽  
Dna Demethylation ◽  
Skin Wound Healing ◽  
Active Dna Demethylation ◽  
Diabetic Wound Healing ◽  
Base Excision

Abstract Wound healing in diabetic skin is impaired by excessive activation of matrix metalloproteinase-9 (MMP-9). MMP-9 transcription is activated by Ten-eleven translocation 2 (TET2), a well-known DNA demethylation protein that induces MMP-9 promoter demethylation in diabetic skin tissues. However, how TET2 is targeted to specific loci in the MMP-9 promoter is unknown. Here, we identified a TET2-interacting long noncoding RNA (TETILA) that is upregulated in human diabetic skin tissues. TETILA regulates TET2 subcellular localization and enzymatic activity, indirectly activating MMP-9 promoter demethylation. TETILA also recruits thymine-DNA glycosylase (TDG), which simultaneously interacts with TET2, for base excision repair-mediated MMP-9 promoter demethylation. Together, our results suggest that the TETILA serves as a genomic homing signal for TET2-mediated demethylation specific loci in MMP-9 promoter, thereby disrupting the process of diabetic skin wound healing.

scholarly journals Estradiol-Induced Epigenetically Mediated Mechanisms and Regulation of Gene Expression

2020 ◽  
Vol 21 (9) ◽  
pp. 3177 ◽  
Author(s):  
Tamás Kovács ◽  
Edina Szabó-Meleg ◽  
István M. Ábrahám
Keyword(s):  
Dna Methylation ◽  
Chromatin Remodeling ◽  
Gene Transcription ◽  
Regulation Of Gene Expression ◽  
Dna Demethylation ◽  
Gonadal Hormone ◽  
Active Dna Demethylation ◽  
Physiological Processes ◽  
Chromatin Remodeling Complexes ◽  
17Β Estradiol

Gonadal hormone 17β-estradiol (E2) and its receptors are key regulators of gene transcription by binding to estrogen responsive elements in the genome. Besides the classical genomic action, E2 regulates gene transcription via the modification of epigenetic marks on DNA and histone proteins. Depending on the reaction partner, liganded estrogen receptor (ER) promotes DNA methylation at the promoter or enhancer regions. In addition, ERs are important regulators of passive and active DNA demethylation. Furthermore, ERs cooperating with different histone modifying enzymes and chromatin remodeling complexes alter gene transcription. In this review, we survey the basic mechanisms and interactions between estrogen receptors and DNA methylation, demethylation and histone modification processes as well as chromatin remodeling complexes. The particular relevance of these mechanisms to physiological processes in memory formation, embryonic development, spermatogenesis and aging as well as in pathophysiological changes in carcinogenesis is also discussed.

scholarly journals A novel protein complex that regulates active DNA demethylation in Arabidopsis

2020 ◽  
Author(s):  
Pan Liu ◽  
Wen-Feng Nie ◽  
Xiansong Xiong ◽  
Yuhua Wang ◽  
Yuwei Jiang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Protein Complex ◽  
Excision Repair ◽  
Dna Demethylation ◽  
Loss Of Function ◽  
Dna Hypermethylation ◽  
Active Dna Demethylation ◽  
Domain Protein ◽  
Genomic Regions

SUMMARYActive DNA demethylation is critical for altering DNA methylation patterns and regulating gene expression. The 5-methylcytosine DNA glycosylase/lyase ROS1 initiates a base excision repair pathway for active DNA demethylation and is required for the prevention of DNA hypermethylation at thousands of genomic regions in Arabidopsis. How ROS1 is regulated and targeted to specific genomic regions is not well understood. Here, we report the discovery of an Arabidopsis protein complex that contains ROS1, regulates ROS1 gene expression, and likely targets the ROS1 protein to specific genomic regions. ROS1 physically interacts with a WD40 domain protein (RWD40), which in turn interacts with a methyl-DNA binding protein (RMB1) as well as with a zinc finger and homeobox domain protein (RHD1). RMB1 binds to DNA that is methylated in any sequence context, and this binding is necessary for its function in vivo.Loss-of-function mutations in RWD40, RMB1, or RHD1 cause DNA hypermethylation at several tested genomic regions independently of the known ROS1 regulator IDM1. Because the hypermethylated genomic regions include the DNA methylation monitoring sequence in the ROS1 promoter, plants mutated in RWD40, RMB1, or RHD1 show increased ROS1 expression. Importantly, ROS1 binding to the ROS1 promoter requires RWD40, RMB1, and RHD1, suggesting that this complex dictates ROS1 targeting to this locus. Our results demonstrate that ROS1 forms a protein complex with RWD40, RMB1, and RHD1, and that this novel complex regulates active DNA demethylation at several endogenous loci in Arabidopsis.

scholarly journals Somatic DNA demethylation generates tissue-specific methylation states and impacts flowering time

2021 ◽  
Author(s):  
Ben P Williams ◽  
Linsdey A Bechen ◽  
Deborah A Pohlmann ◽  
Mary Gehring
Keyword(s):  
Cytosine Methylation ◽  
Epigenetic Modification ◽  
Dna Demethylation ◽  
Dna Glycosylases ◽  
Wild Type ◽  
Gene Body Methylation ◽  
Tissue Specific ◽  
Coding Regions ◽  
Active Dna Demethylation ◽  
Somatic Tissues

Cytosine methylation is a reversible epigenetic modification to DNA. In plants, removal of cytosine methylation is accomplished by the four members of the DME family of 5-methylcytosine DNA glycosylases. Demethylation by DME is critical for seed development. Consequently, determining the function of the entire gene family in somatic tissues by mutant analysis has not been possible. Here, we bypassed the reproductive defects of dme mutants to create somatic quadruple homozygous mutants of the entire DME family. dme; ros1; dml2; dml3 (drdd) leaves exhibit hypermethylated genomes compared to both wild-type plants and rdd triple mutants, indicating functional redundancy among all four demethylases. Targets of demethylation include regions co-targeted by RNA-directed DNA methylation and, surprisingly, CG gene body methylation, indicating dynamic methylation at these little-understood sites. Additionally, many tissue-specific methylation differences are absent in drdd, suggesting a role for active demethylation in generating divergent epigenetic states across wild-type tissues. Furthermore, drdd plants display a striking early flowering phenotype, which is associated with 5′ hypermethylation and transcriptional down-regulation of FLOWERING LOCUS C. Active DNA demethylation is therefore required for proper methylation patterning across somatic tissues and defines the epigenetic landscape of both intergenic and coding regions.

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