scholarly journals Local CpG density affects the trajectory of age-associated epigenetic changes

2021 ◽  
Author(s):  
Jonathan Higham ◽  
Qian Zhang ◽  
Rosie M Walker ◽  
Sarah E Harris ◽  
David M Howard ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Sequence ◽  
Genome Stability ◽  
Molecular Mechanisms ◽  
Epigenetic Mark ◽  
Epigenetic Changes ◽  
Snp Data ◽  
Local Sequence ◽  
Methylation Patterns

DNA methylation is an epigenetic mark associated with gene repression and genome stability. Its pattern in the genome is disrupted with age and these changes can be used to statistically predict age with epigenetic clocks. Rates of aging inferred from these clocks correlate with human health. However, the molecular mechanisms underpinning age-associated DNA methylation changes are unknown. Local DNA sequence plays a strong role in programming DNA methylation levels at individual loci independently of age, but its influence on age-associated DNA methylation changes is unknown. We analysed longitudinal human DNA methylation trajectories at 345,895 CpGs from 600 individuals aged between 67 and 80 to understand the factors responsible for age-associated epigenetic changes at individual CpGs in the genome. We show that changes in methylation with age are especially apparent at 8,322 low CpG density loci. Using SNP data from the same individuals we demonstrate that DNA methylation trajectories are affected by local sequence polymorphisms at 1,487 loci with low CpG density. More generally, we find that local CpG density is a strong determinant of a CpG's methylation trajectory and that CpGs located in low CpG density regions are particularly prone to change. Overall, our results demonstrate that local DNA sequence influences age-associated DNA methylation changes in humans in vivo. We suggest that this occurs because interactions between CpGs reinforce maintenance of methylation patterns in CpG dense regions.

scholarly journals Epigenetic aging of human hematopoietic cells is not accelerated upon transplantation into mice

2018 ◽  
Author(s):  
Joana Frobel ◽  
Susann Rahmig ◽  
Julia Franzen ◽  
Claudia Waskow ◽  
Wolfgang Wagner
Keyword(s):  
Dna Methylation ◽  
Epigenetic Clock ◽  
Epigenetic Changes ◽  
Hematopoietic Stem ◽  
Hematopoietic Development ◽  
Immunodeficient Mice ◽  
Epigenetic Aging ◽  
Normal Human ◽  
Methylation Patterns

AbstractTransplantation of human hematopoietic stem cells into immunodeficient mice provides a powerful in vivo model system to gain functional insights into hematopoietic differentiation. So far, it remains unclear if epigenetic changes of normal human hematopoiesis are recapitulated upon engraftment into such “humanized mice”. Mice have a much shorter life expectancy than men, and therefore we hypothesized that the xenogeneic environment might greatly accelerate the epigenetic clock. We demonstrate that genome-wide DNA methylation patterns of normal human hematopoietic development are indeed recapitulated upon engraftment in mice – particularly those of normal early B cell progenitor cells. Furthermore, we tested three epigenetic aging signatures and none of them indicated that the murine environment accelerated age-associated DNA methylation changes. These results demonstrate that the murine transplantation model overall recapitulates epigenetic changes of human hematopoietic development, whereas epigenetic aging seems to occur cell intrinsically.

scholarly journals Selective Anchoring of DNA Methyltransferases 3A and 3B to Nucleosomes Containing Methylated DNA

2009 ◽  
Vol 29 (19) ◽  
pp. 5366-5376 ◽  
Author(s):  
Shinwu Jeong ◽  
Gangning Liang ◽  
Shikhar Sharma ◽  
Joy C. Lin ◽  
Si Ho Choi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Molecular Mechanisms ◽  
Dna Methyltransferases ◽  
Micrococcal Nuclease ◽  
Nuclear Antigen ◽  
Heterochromatin Protein 1 ◽  
Histone Deacetylase 1 ◽  
Methylation Patterns

ABSTRACT Proper DNA methylation patterns are essential for mammalian development and differentiation. DNA methyltransferases (DNMTs) primarily establish and maintain global DNA methylation patterns; however, the molecular mechanisms for the generation and inheritance of methylation patterns are still poorly understood. We used sucrose density gradients of nucleosomes prepared by partial and maximum micrococcal nuclease digestion, coupled with Western blot analysis to probe for the interactions between DNMTs and native nucleosomes. This method allows for analysis of the in vivo interactions between the chromatin modification enzymes and their actual nucleosomal substrates in the native state. We show that little free DNA methyltransferase 3A and 3B (DNMT3A/3B) exist in the nucleus and that almost all of the cellular contents of DNMT3A/3B, but not DNMT1, are strongly anchored to a subset of nucleosomes. This binding of DNMT3A/3B does not require the presence of other well-known chromatin-modifying enzymes or proteins, such as proliferating cell nuclear antigen, heterochromatin protein 1, methyl-CpG binding protein 2, Enhancer of Zeste homolog 2, histone deacetylase 1, and UHRF1, but it does require an intact nucleosomal structure. We also show that nucleosomes containing methylated SINE and LINE elements and CpG islands are the main sites of DNMT3A/3B binding. These data suggest that inheritance of DNA methylation requires cues from the chromatin component in addition to hemimethylation.

scholarly journals DNA methylation mediated RSPO2 to promote follicular development in mammals

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Xiaofeng Zhou ◽  
Yingting He ◽  
Nian Li ◽  
Guofeng Bai ◽  
Xiangchun Pan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Methylation Level ◽  
Molecular Mechanisms ◽  
Cpg Island ◽  
Wnt Signaling Pathway ◽  
Follicular Development ◽  
Expression Level

AbstractIn female mammals, the proliferation, apoptosis, and estradiol-17β (E2) secretion of granulosa cells (GCs) have come to decide the fate of follicles. DNA methylation and RSPO2 gene of Wnt signaling pathway have been reported to involve in the survival of GCs and follicular development. However, the molecular mechanisms for how DNA methylation regulates the expression of RSPO2 and participates in the follicular development are not clear. In this study, we found that the mRNA and protein levels of RSPO2 significantly increased during follicular development, but the DNA methylation level of RSPO2 promoter decreased gradually. Inhibition of DNA methylation or DNMT1 knockdown could decrease the methylation level of CpG island (CGI) in RSPO2 promoter and upregulate the expression level of RSPO2 in porcine GCs. The hypomethylation of −758/−749 and −563/−553 regions in RSPO2 promoter facilitated the occupancy of transcription factor E2F1 and promoted the transcriptional activity of RSPO2. Moreover, RSPO2 promoted the proliferation of GCs with increasing the expression level of PCNA, CDK1, and CCND1 and promoted the E2 secretion of GCs with increasing the expression level of CYP19A1 and HSD17B1 and inhibited the apoptosis of GCs with decreasing the expression level of Caspase3, cleaved Caspase3, cleaved Caspase8, cleaved Caspase9, cleaved PARP, and BAX. In addition, RSPO2 knockdown promoted the apoptosis of GCs, blocked the development of follicles, and delayed the onset of puberty with decreasing the expression level of Wnt signaling pathway-related genes (LGR4 and CTNNB1) in vivo. Taken together, the hypomethylation of −758/−749 and −563/−553 regions in RSPO2 promoter facilitated the occupancy of E2F1 and enhanced the transcription of RSPO2, which further promoted the proliferation and E2 secretion of GCs, inhibited the apoptosis of GCs, and ultimately ameliorated the development of follicles through Wnt signaling pathway. This study will provide useful information for further exploration on DNA-methylation-mediated RSPO2 pathway during follicular development.

scholarly journals Unraveling the neurotoxicity of titanium dioxide nanoparticles: focusing on molecular mechanisms

2016 ◽  
Vol 7 ◽  
pp. 645-654 ◽  
Author(s):  
Bin Song ◽  
Yanli Zhang ◽  
Jia Liu ◽  
Xiaoli Feng ◽  
Ting Zhou ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Titanium Dioxide ◽  
Molecular Mechanisms ◽  
Titanium Dioxide Nanoparticles ◽  
Brain Dysfunction ◽  
In Vivo Studies ◽  
Cell Components ◽  
New Perspective ◽  
The Brain

Titanium dioxide nanoparticles (TiO2 NPs) possess unique characteristics and are widely used in many fields. Numerous in vivo studies, exposing experimental animals to these NPs through systematic administration, have suggested that TiO2 NPs can accumulate in the brain and induce brain dysfunction. Nevertheless, the exact mechanisms underlying the neurotoxicity of TiO2 NPs remain unclear. However, we have concluded from previous studies that these mechanisms mainly consist of oxidative stress (OS), apoptosis, inflammatory response, genotoxicity, and direct impairment of cell components. Meanwhile, other factors such as disturbed distributions of trace elements, disrupted signaling pathways, dysregulated neurotransmitters and synaptic plasticity have also been shown to contribute to neurotoxicity of TiO2 NPs. Recently, studies on autophagy and DNA methylation have shed some light on possible mechanisms of nanotoxicity. Therefore, we offer a new perspective that autophagy and DNA methylation could contribute to neurotoxicity of TiO2 NPs. Undoubtedly, more studies are needed to test this idea in the future. In short, to fully understand the health threats posed by TiO2 NPs and to improve the bio-safety of TiO2 NPs-based products, the neurotoxicity of TiO2 NPs must be investigated comprehensively through studying every possible molecular mechanism.

TMOD-02. GENERATION OF A NOVEL MOUSE MODEL FOR BRAIN TUMORS OF THE DNA METHYLATION CLASS “GBM MYCN”

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi215-vi216
Author(s):  
Melanie Schoof ◽  
Carolin Göbel ◽  
Dörthe Holdhof ◽  
Sina Al-Kershi ◽  
Ulrich Schüller
Keyword(s):  
Dna Methylation ◽  
Brain Tumors ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Tumor Development ◽  
Model Systems ◽  
Preclinical Research ◽  
Human Gbm

Abstract DNA methylation based classification of brain tumors has revealed a high heterogeneity between tumors and led to the description of multiple distinct subclasses. The increasing subdivision of tumors can help to understand molecular mechanisms of tumor development and to improve therapy if appropriate model systems for preclinical research are available. Multiple recent publications have described a subgroup of pediatric glioblastoma which is clearly separable from other pediatric and adult glioblastoma in its DNA methylation profile (GBM MYCN). Many cases in this group are driven by MYCN amplifications and harbor TP53 mutations. These tumors almost exclusively occur in children and were further described as highly aggressive with a median overall survival of only 14 months. In order to further investigate the biology and treatment options of these tumors, we generated hGFAP-cre::TP53 Fl/Fl ::lsl-MYCN mice. These mice carry a loss of TP53 and show aberrant MYCN expression in neural precursors of the central nervous system. The animals develop large forebrain tumors within the first 80 days of life with 100 % penetrance. These tumors resemble human GBM MYCN tumors histologically and are sensitive to AURKA and ATR inhibitors in vitro. We believe that further characterization of the model and in vivo treatment studies will pave the way to improve treatment of patients with these highly aggressive tumors.

scholarly journals Dynamic DNA Methylation in Plant Growth and Development

2018 ◽  
Vol 19 (7) ◽  
pp. 2144 ◽  
Author(s):  
Arthur Bartels ◽  
Qiang Han ◽  
Pooja Nair ◽  
Liam Stacey ◽  
Hannah Gaynier ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Plant Growth ◽  
Growth And Development ◽  
Genome Stability ◽  
Epigenetic Modification ◽  
Plant Growth And Development ◽  
Complex Dynamic ◽  
Dynamic Changes ◽  
The Common ◽  
Methylation Patterns

DNA methylation is an epigenetic modification required for transposable element (TE) silencing, genome stability, and genomic imprinting. Although DNA methylation has been intensively studied, the dynamic nature of methylation among different species has just begun to be understood. Here we summarize the recent progress in research on the wide variation of DNA methylation in different plants, organs, tissues, and cells; dynamic changes of methylation are also reported during plant growth and development as well as changes in response to environmental stresses. Overall DNA methylation is quite diverse among species, and it occurs in CG, CHG, and CHH (H = A, C, or T) contexts of genes and TEs in angiosperms. Moderately expressed genes are most likely methylated in gene bodies. Methylation levels decrease significantly just upstream of the transcription start site and around transcription termination sites; its levels in the promoter are inversely correlated with the expression of some genes in plants. Methylation can be altered by different environmental stimuli such as pathogens and abiotic stresses. It is likely that methylation existed in the common eukaryotic ancestor before fungi, plants and animals diverged during evolution. In summary, DNA methylation patterns in angiosperms are complex, dynamic, and an integral part of genome diversity after millions of years of evolution.

scholarly journals Diet quality associated peripheral blood DNA methylation signatures

2020 ◽  
Vol 79 (OCE2) ◽  
Author(s):  
Jiantao Ma ◽  
Casey Rebholz ◽  
Kim Braun ◽  
Lindsay Reynolds ◽  
Stella Aslibekyan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Diet Quality ◽  
Peripheral Blood ◽  
Molecular Mechanisms ◽  
Healthy Eating Index ◽  
European Ancestry ◽  
P Value ◽  
Primary Analysis ◽  
Habitual Diet ◽  
Methylation Patterns

AbstractLeukocyte DNA methylation patterns associated with habitual diet may reveal molecular mechanisms involved in the pathogenesis of diet-related chronic diseases and highlight targets for prevention and treatment. We aimed to examine peripheral blood derived leukocyte DNA methylation signatures associated with diet quality. We meta-analyzed epigenome-wide associations between diet quality and DNA methylation levels at over 400,000 cytosine-guanine dinucleotides (CpGs). We conducted analysis primarily in 6,662 European ancestry (EA) participants and secondarily in a group additionally including 3,062 participants of non-European ancestry from five population-based cohort studies. DNA methylation profiles were measured in whole blood, CD4 + T-cells, or CD14 + monocytes. We used food frequency questionnaires to assess habitual intake and constructed two diet quality scores: the Mediterranean-style diet score (MDS) and Alternative Healthy Eating Index (AHEI). Our primary analysis identified 32 diet-associated CpGs, 12 CpGs for MDS and 24 CpGs for AHEI (at FDR < 0.05, corresponding p-values = 1.2×10-6 and 3.1×10-6, respectively) in EA participants. Four of these CpGs were associated with both MDS and AHEI. In addition, Mendelian randomization analysis indicated that seven diet-associated CpGs were causally linked to at least one of the CVD risk factors. For example, hypermethylation of cg11250194 (FADS2), which was associated with higher diet quality scores, was also associated with lower fasting triglycerides concentrations (p-value = 1.5×10-14) and higher high-density lipoprotein cholesterol concentrations (p-value = 1.7×10-8). Transethnic meta-analysis identified nine additional CpGs associated with diet quality (either MDS or AHEI) at FDR < 0.05. Overall quality of habitual diet was associated with differential peripheral leukocyte DNA methylation levels of 32 CpGs in EA participants. The diet-associated CpGs may serve as biomarkers and targets for preventive measures in CVD health. Future studies are warranted to examine diet-associated DNA methylation patterns in larger, ethnically diverse study samples.

scholarly journals DNA methylation and gene expression changes derived from assisted reproductive technologies can be decreased by reproductive fluids

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Sebastian Canovas ◽  
Elena Ivanova ◽  
Raquel Romar ◽  
Soledad García-Martínez ◽  
Cristina Soriano-Úbeda ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Assisted Reproductive Technologies ◽  
Reproductive Technologies ◽  
Cell Number ◽  
Rna Seq ◽  
Methylation Analysis ◽  
Number Of Children ◽  
Methylation Patterns

The number of children born since the origin of Assisted Reproductive Technologies (ART) exceeds 5 million. The majority seem healthy, but a higher frequency of defects has been reported among ART-conceived infants, suggesting an epigenetic cost. We report the first whole-genome DNA methylation datasets from single pig blastocysts showing differences between in vivo and in vitro produced embryos. Blastocysts were produced in vitro either without (C-IVF) or in the presence of natural reproductive fluids (Natur-IVF). Natur-IVF embryos were of higher quality than C-IVF in terms of cell number and hatching ability. RNA-Seq and DNA methylation analyses showed that Natur-IVF embryos have expression and methylation patterns closer to in vivo blastocysts. Genes involved in reprogramming, imprinting and development were affected by culture, with fewer aberrations in Natur-IVF embryos. Methylation analysis detected methylated changes in C-IVF, but not in Natur-IVF, at genes whose methylation could be critical, such as IGF2R and NNAT.

scholarly journals Impact of a hypomorphic Artemis disease allele on lymphocyte development, DNA end processing, and genome stability

2009 ◽  
Vol 206 (4) ◽  
pp. 893-908 ◽  
Author(s):  
Ying Huang ◽  
William Giblin ◽  
Martina Kubec ◽  
Gerwin Westfield ◽  
Jordan St. Charles ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Genome Stability ◽  
Molecular Mechanisms ◽  
Translation Termination ◽  
Severe Combined Immunodeficiency ◽  
Strand Break ◽  
Hypomorphic Mutation ◽  
C Terminus ◽  
B And T Lymphocytes

Artemis was initially discovered as the gene inactivated in human radiosensitive T−B− severe combined immunodeficiency, a syndrome characterized by the absence of B and T lymphocytes and cellular hypersensitivity to ionizing radiation. Hypomorphic Artemis alleles have also been identified in patients and are associated with combined immunodeficiencies of varying severity. We examine the molecular mechanisms underlying a syndrome of partial immunodeficiency caused by a hypomorphic Artemis allele using the mouse as a model system. This mutation, P70, leads to premature translation termination that deletes a large portion of a nonconserved C terminus. We find that homozygous Artemis-P70 mice exhibit reduced numbers of B and T lymphocytes, thereby recapitulating the patient phenotypes. The hypomorphic mutation results in impaired end processing during the lymphoid-specific DNA rearrangement known as V(D)J recombination, defective double-strand break repair, and increased chromosomal instability. Biochemical analyses reveal that the Artemis-P70 mutant protein interacts with the DNA-dependent protein kinase catalytic subunit and retains significant, albeit reduced, exo- and endonuclease activities but does not undergo phosphorylation. Together, our findings indicate that the Artemis C terminus has critical in vivo functions in ensuring efficient V(D)J rearrangements and maintaining genome integrity.

scholarly journals Establishment and Maintenance of Genomic Methylation Patterns in Mouse Embryonic Stem Cells by Dnmt3a and Dnmt3b

2003 ◽  
Vol 23 (16) ◽  
pp. 5594-5605 ◽  
Author(s):  
Taiping Chen ◽  
Yoshihide Ueda ◽  
Jonathan E. Dodge ◽  
Zhenjuan Wang ◽  
En Li
Keyword(s):  
Dna Methylation ◽  
De Novo ◽  
Es Cells ◽  
Embryonic Stem ◽  
Single Copy ◽  
Dna Methyltransferases ◽  
Methylation Patterns ◽  
Genomic Methylation ◽  
De Novo Methylation

ABSTRACT We have previously shown that the DNA methyltransferases Dnmt3a and Dnmt3b carry out de novo methylation of the mouse genome during early postimplantation development and of maternally imprinted genes in the oocyte. In the present study, we demonstrate that Dnmt3a and Dnmt3b are also essential for the stable inheritance, or “maintenance,” of DNA methylation patterns. Inactivation of both Dnmt3a and Dnmt3b in embryonic stem (ES) cells results in progressive loss of methylation in various repeats and single-copy genes. Interestingly, introduction of the Dnmt3a, Dnmt3a2, and Dnmt3b1 isoforms back into highly demethylated mutant ES cells restores genomic methylation patterns; these isoforms appear to have both common and distinct DNA targets, but they all fail to restore the maternal methylation imprints. In contrast, overexpression of Dnmt1 and Dnmt3b3 failed to restore DNA methylation patterns due to their inability to catalyze de novo methylation in vivo. We also show that hypermethylation of genomic DNA by Dnmt3a and Dnmt3b is necessary for ES cells to form teratomas in nude mice. These results indicate that genomic methylation patterns are determined partly through differential expression of different Dnmt3a and Dnmt3b isoforms.

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