scholarly journals Duplicated dnmt3aa and dnmt3ab DNA Methyltransferase Genes Play Essential and Non-Overlapped Functions on Modulating Behavioral Control in Zebrafish

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1322
Author(s):  
Yu-Heng Lai ◽  
Gilbert Audira ◽  
Sung-Tzu Liang ◽  
Petrus Siregar ◽  
Michael Edbert Suryanto ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Social Interaction ◽  
Dna Methyltransferase ◽  
Short Term Memory ◽  
De Novo ◽  
Behavioral Control ◽  
Methylation Pattern ◽  
Color Preference ◽  
Fear Response ◽  
Behavioral Alterations

DNA methylation plays several roles in regulating neuronal proliferation, differentiation, and physiological functions. The major de novo methyltransferase, DNMT3, controls the DNA methylation pattern in neurons according to environmental stimulations and behavioral regulations. Previous studies demonstrated that knockout of Dnmt3 induced mouse anxiety; however, controversial results showed that activation of Dnmt3 causes anxiolytic behavior. Thus, an alternative animal model to clarify Dnmt3 on modulating behavior is crucial. Therefore, we aimed to establish a zebrafish (Danio rerio) model to clarify the function of dnmt3 on fish behavior by behavioral endpoint analyses. We evaluated the behaviors of the wild type, dnmt3aa, and dnmt3ab knockout (KO) fish by the novel tank, mirror biting, predator avoidance, social interaction, shoaling, circadian rhythm locomotor activity, color preference, and short-term memory tests. The results indicated that the dnmt3aa KO fish possessed abnormal exploratory behaviors and less fear response to the predator. On the other hand, dnmt3ab KO fish displayed less aggression, fear response to the predator, and interests to interact with their conspecifics, loosen shoaling formation, and dysregulated color preference index ranking. Furthermore, both knockout fishes showed higher locomotion activity during the night cycle, which is a sign of anxiety. However, changes in some neurotransmitter levels were observed in the mutant fishes. Lastly, whole-genome DNA methylation sequencing demonstrates a potential network of Dnmt3a proteins that is responsive to behavioral alterations. To sum up, the results suggested that the dnmt3aa KO or dnmt3ab KO fish display anxiety symptoms, which supported the idea that Dnmt3 modulates the function involved in emotional control, social interaction, and cognition.

scholarly journals Oxidative DNA Damage Modulates DNA Methylation Pattern in Human Breast Cancer 1 (BRCA1) Gene via the Crosstalk between DNA Polymerase β and a de novo DNA Methyltransferase

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 225 ◽  
Author(s):  
Zhongliang Jiang ◽  
Yanhao Lai ◽  
Jill M. Beaver ◽  
Pawlos S. Tsegay ◽  
Ming-Lang Zhao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Dna Damage ◽  
Dna Polymerase ◽  
Dna Methyltransferase ◽  
Oxidative Dna Damage ◽  
De Novo ◽  
Brca1 Gene ◽  
Methylation Pattern ◽  
Dna Polymerase Β

DNA damage and base excision repair (BER) are actively involved in the modulation of DNA methylation and demethylation. However, the underlying molecular mechanisms remain unclear. In this study, we seek to understand the mechanisms by exploring the effects of oxidative DNA damage on the DNA methylation pattern of the tumor suppressor breast cancer 1 (BRCA1) gene in the human embryonic kidney (HEK) HEK293H cells. We found that oxidative DNA damage simultaneously induced DNA demethylation and generation of new methylation sites at the CpGs located at the promoter and transcribed regions of the gene ranging from −189 to +27 in human cells. We demonstrated that DNA damage-induced demethylation was mediated by nucleotide misincorporation by DNA polymerase β (pol β). Surprisingly, we found that the generation of new DNA methylation sites was mediated by coordination between pol β and the de novo DNA methyltransferase, DNA methyltransferase 3b (DNMT3b), through the interaction between the two enzymes in the promoter and encoding regions of the BRCA1 gene. Our study provides the first evidence that oxidative DNA damage can cause dynamic changes in DNA methylation in the BRCA1 gene through the crosstalk between BER and de novo DNA methylation.

scholarly journals Epigenetic Changes in Host Ribosomal DNA Promoter Induced by an Asymptomatic Plant Virus Infection

Biology ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 91 ◽  
Author(s):  
Miryam Pérez-Cañamás ◽  
Elizabeth Hevia ◽  
Carmen Hernández
Keyword(s):  
Gene Silencing ◽  
Ribosomal Dna ◽  
Plant Virus ◽  
Dna Methyltransferase ◽  
Cytosine Methylation ◽  
De Novo ◽  
Methylation Pattern ◽  
Transcriptional Gene Silencing ◽  
Post Transcriptional Gene Silencing ◽  
The Impact

DNA cytosine methylation is one of the main epigenetic mechanisms in higher eukaryotes and is considered to play a key role in transcriptional gene silencing. In plants, cytosine methylation can occur in all sequence contexts (CG, CHG, and CHH), and its levels are controlled by multiple pathways, including de novo methylation, maintenance methylation, and demethylation. Modulation of DNA methylation represents a potentially robust mechanism to adjust gene expression following exposure to different stresses. However, the potential involvement of epigenetics in plant-virus interactions has been scarcely explored, especially with regard to RNA viruses. Here, we studied the impact of a symptomless viral infection on the epigenetic status of the host genome. We focused our attention on the interaction between Nicotiana benthamiana and Pelargonium line pattern virus (PLPV, family Tombusviridae), and analyzed cytosine methylation in the repetitive genomic element corresponding to ribosomal DNA (rDNA). Through a combination of bisulfite sequencing and RT-qPCR, we obtained data showing that PLPV infection gives rise to a reduction in methylation at CG sites of the rDNA promoter. Such a reduction correlated with an increase and decrease, respectively, in the expression levels of some key demethylases and of MET1, the DNA methyltransferase responsible for the maintenance of CG methylation. Hypomethylation of rDNA promoter was associated with a five-fold augmentation of rRNA precursor levels. The PLPV protein p37, reported as a suppressor of post-transcriptional gene silencing, did not lead to the same effects when expressed alone and, thus, it is unlikely to act as suppressor of transcriptional gene silencing. Collectively, the results suggest that PLPV infection as a whole is able to modulate host transcriptional activity through changes in the cytosine methylation pattern arising from misregulation of methyltransferases/demethylases balance.

scholarly journals UVR8 interacts with de novo DNA methyltransferase and suppresses DNA methylation in Arabidopsis

Nature Plants ◽  
2021 ◽  
Vol 7 (2) ◽  
pp. 184-197
Author(s):  
Jianjun Jiang ◽  
Jie Liu ◽  
Dean Sanders ◽  
Shuiming Qian ◽  
Wendan Ren ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo

scholarly journals Structural insights into CpG-specific DNA methylation by human DNA methyltransferase 3B

2020 ◽  
Vol 48 (7) ◽  
pp. 3949-3961 ◽  
Author(s):  
Chien-Chu Lin ◽  
Yi-Ping Chen ◽  
Wei-Zen Yang ◽  
James C K Shen ◽  
Hanna S Yuan
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Cytosine Methylation ◽  
Catalytic Domain ◽  
De Novo ◽  
Water Channel ◽  
Dna Methyltransferases ◽  
Structural Basis ◽  
Cpg Sites ◽  
Methylation Patterns

Abstract DNA methyltransferases are primary enzymes for cytosine methylation at CpG sites of epigenetic gene regulation in mammals. De novo methyltransferases DNMT3A and DNMT3B create DNA methylation patterns during development, but how they differentially implement genomic DNA methylation patterns is poorly understood. Here, we report crystal structures of the catalytic domain of human DNMT3B–3L complex, noncovalently bound with and without DNA of different sequences. Human DNMT3B uses two flexible loops to enclose DNA and employs its catalytic loop to flip out the cytosine base. As opposed to DNMT3A, DNMT3B specifically recognizes DNA with CpGpG sites via residues Asn779 and Lys777 in its more stable and well-ordered target recognition domain loop to facilitate processive methylation of tandemly repeated CpG sites. We also identify a proton wire water channel for the final deprotonation step, revealing the complete working mechanism for cytosine methylation by DNMT3B and providing the structural basis for DNMT3B mutation-induced hypomethylation in immunodeficiency, centromere instability and facial anomalies syndrome.

scholarly journals Identification of transcription termination defects at DNA hypomethylated transcription termination sites in DNA methyltransferase 3a-deficient vertebrates.

2021 ◽  
Author(s):  
Masaki Shirai ◽  
Takuya Nara ◽  
Haruko Takahashi ◽  
Kazuya Takayama ◽  
Yuan Chen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Es Cells ◽  
Transcription Termination ◽  
Promoter Regions ◽  
Zebrafish Model ◽  
Body Regions ◽  
Chimeric Transcripts ◽  
Dna Methyltransferase 3A

CpG methylation in genomic DNA is well known as a repressive epigenetic marker in eukaryotic transcription, and DNA methylation of the promoter regions is correlated with silencing of gene expression. In contrast to the promoter regions, the function of DNA methylation during transcription termination remains to be elucidated. A recent study has revealed that mouse DNA methyltransferase 3a (Dnmt3a) mainly functions in de novo methylation in the promoter and gene body regions (including transcription termination sites (TTSs)) during development. To investigate the relationship between DNA methylation overlapping the TTSs and transcription termination, we employed two strategies: informatic analysis using already deposited datasets of Dnmt3a-/- mouse cells and the zebrafish model system. Bioinformatic analysis using methylome and transcriptome data showed that hypomethylated differentially methylated regions overlapping the TTSs were associated with increased read counts and chimeric transcripts downstream of TTSs in Dnmt3a-/- Agouti-related protein neurons, but not in Dnmt3a-/- ES cells and MEFs. We experimentally detected increased read-through and chimeric transcripts downstream of hypomethylated TTSs in zebrafish maternal-zygotic dnmt3aa-/- mutants. This study is the first to identify transcription termination defects in DNA hypomethylated TTSs in Dnmt3a-/- vertebrates.

scholarly journals Brown Fat Dnmt3b Deficiency Ameliorates Obesity in Female Mice

Life ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1325
Author(s):  
Fenfen Li ◽  
Xin Cui ◽  
Jia Jing ◽  
Shirong Wang ◽  
Huidong Shi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Energy Expenditure ◽  
Knockout Mice ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Brown Fat ◽  
Chow Diet ◽  
Female Mice ◽  
Diet Induced Obesity

Obesity results from a chronic energy imbalance due to energy intake exceeding energy expenditure. Activation of brown fat thermogenesis has been shown to combat obesity. Epigenetic regulation, including DNA methylation, has emerged as a key regulator of brown fat thermogenic function. Here we aimed to study the role of Dnmt3b, a DNA methyltransferase involved in de novo DNA methylation, in the regulation of brown fat thermogenesis and obesity. We found that the specific deletion of Dnmt3b in brown fat promotes the thermogenic and mitochondrial program in brown fat, enhances energy expenditure, and decreases adiposity in female mice fed a regular chow diet. With a lean phenotype, the female knockout mice also exhibit increased insulin sensitivity. In addition, Dnmt3b deficiency in brown fat also prevents diet-induced obesity and insulin resistance in female mice. Interestingly, our RNA-seq analysis revealed an upregulation of the PI3K-Akt pathway in the brown fat of female Dnmt3b knockout mice. However, male Dnmt3b knockout mice have no change in their body weight, suggesting the existence of sexual dimorphism in the brown fat Dnmt3b knockout model. Our data demonstrate that Dnmt3b plays an important role in the regulation of brown fat function, energy metabolism and obesity in female mice.

scholarly journals Epimutations are associated with CHROMOMETHYLASE 3-induced de novo DNA methylation

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Jered M Wendte ◽  
Yinwen Zhang ◽  
Lexiang Ji ◽  
Xiuling Shi ◽  
Rashmi R Hazarika ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Plant Species ◽  
Dna Methyltransferase ◽  
Constitutive Heterochromatin ◽  
De Novo ◽  
Flowering Plant ◽  
Gene Body ◽  
Gene Body Methylation ◽  
Mechanistic Basis ◽  
Flowering Plant Species

In many plant species, a subset of transcribed genes are characterized by strictly CG-context DNA methylation, referred to as gene body methylation (gbM). The mechanisms that establish gbM are unclear, yet flowering plant species naturally without gbM lack the DNA methyltransferase, CMT3, which maintains CHG (H = A, C, or T) and not CG methylation at constitutive heterochromatin. Here, we identify the mechanistic basis for gbM establishment by expressing CMT3 in a species naturally lacking CMT3. CMT3 expression reconstituted gbM through a progression of de novo CHG methylation on expressed genes, followed by the accumulation of CG methylation that could be inherited even following loss of the CMT3 transgene. Thus, gbM likely originates from the simultaneous targeting of loci by pathways that promote euchromatin and heterochromatin, which primes genes for the formation of stably inherited epimutations in the form of CG DNA methylation.

scholarly journals Persistent epigenetic memory impedes rescue of the telomeric phenotype in human ICF iPSCs following DNMT3B correction

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Shir Toubiana ◽  
Miriam Gagliardi ◽  
Mariarosaria Papa ◽  
Roberta Manco ◽  
Maty Tzukerman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Pharmacological Intervention ◽  
Icf Syndrome ◽  
Genome Wide ◽  
Mammalian Genomes ◽  
Induced Pluripotent ◽  
Methylation Patterns

DNA methyltransferase 3B (DNMT3B) is the major DNMT that methylates mammalian genomes during early development. Mutations in human DNMT3B disrupt genome-wide DNA methylation patterns and result in ICF syndrome type 1 (ICF1). To study whether normal DNA methylation patterns may be restored in ICF1 cells, we corrected DNMT3B mutations in induced pluripotent stem cells from ICF1 patients. Focusing on repetitive regions, we show that in contrast to pericentromeric repeats, which reacquire normal methylation, the majority of subtelomeres acquire only partial DNA methylation and, accordingly, the ICF1 telomeric phenotype persists. Subtelomeres resistant to de novo methylation were characterized by abnormally high H3K4 trimethylation (H3K4me3), and short-term reduction of H3K4me3 by pharmacological intervention partially restored subtelomeric DNA methylation. These findings demonstrate that the abnormal epigenetic landscape established in ICF1 cells restricts the recruitment of DNMT3B, and suggest that rescue of epigenetic diseases with genome-wide disruptions will demand further manipulation beyond mutation correction.

scholarly journals DNA methylomes and transcriptomes analysis reveal implication of host DNA methylation machinery in BmNPV proliferation in Bombyx mori

BMC Genomics ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Haoling Huang ◽  
Ping Wu ◽  
Shaolun Zhang ◽  
Qi Shang ◽  
Haotong Yin ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bombyx Mori ◽  
Dna Methyltransferase ◽  
Transcript Level ◽  
Research Direction ◽  
Methylation Pattern ◽  
Integrated Analysis ◽  
Infected Cells ◽  
Structural Maintenance Of Chromosomes

Abstract Background Bombyx mori nucleopolyhedrosis virus (BmNPV) is a major pathogen that threatens the sustainability of the sericultural industry. DNA methylation is a widespread gene regulation mode in epigenetics, which plays an important role in host immune response. Until now, little has been known about epigenetic regulation on virus diseases in insects. This study aims to explore the role of DNA methylation in BmNPV proliferation. Results Inhibiting DNA methyltransferase (DNMT) activity of silkworm can suppress BmNPV replication. The integrated analysis of transcriptomes and DNA methylomes in silkworm midguts infected with or without BmNPV showed that both the expression pattern of transcriptome and DNA methylation pattern are changed significantly upon BmNPV infection. A total of 241 differentially methylated regions (DMRs) were observed in BmNPV infected midguts, among which, 126 DMRs were hyper-methylated and 115 DMRs were hypo-methylated. Significant differences in both mRNA transcript level and DNA methylated levels were found in 26 genes. BS-PCR validated the hypermethylation of BGIBMGA014008, a structural maintenance of chromosomes protein gene in the BmNPV-infected midgut. In addition, DNMT inhibition reduced the expression of inhibitor of apoptosis family genes, iap1 from BmNPV, Bmiap2, BmSurvivin1 and BmSurvivin2. Conclusion Our results indicate that DNA methylation plays positive roles in BmNPV proliferation and loss of DNMT activity could induce the apoptosis of infected cells to suppress BmNPV proliferation. Our results may provide a new idea and research direction for the molecular mechanism on insect-virus interaction.

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