scholarly journals Maternal Microdeletion at the H19/Igf2 ICR in Mice Increases Offspring Susceptibility to In Utero Environmental Perturbation

2020 ◽  
Vol 13 ◽  
pp. 251686572097057
Author(s):  
Anandita Pal ◽  
Judy Oakes ◽  
Marwa Elnagheeb ◽  
Folami Y Ideraabdullah
Keyword(s):  
Dna Methylation ◽  
Antibiotic Treatment ◽  
Birth Rate ◽  
Genetic Mutation ◽  
Loss Of Imprinting ◽  
Imprinting Control Region ◽  
Adverse Pregnancy ◽  
Mutant Lines ◽  
Pup Growth ◽  
In Cis

Deficiency of methyl donor nutrients folate, choline, and methionine (methyl deficiency) during gestation can impair fetal development and perturb DNA methylation. Here, we assessed genetic susceptibility to methyl deficiency by comparing effects in wildtype C57BL/6J (B6) mice to mutant mice carrying a 1.3 kb deletion at the H19/Igf2 Imprinting Control Region (ICR) ( H19ICRΔ2,3). The H19ICRΔ2,3 mutation mimics microdeletions observed in Beckwith-Wiedemann syndrome (BWS) patients, who exhibit epimutations in cis that cause loss of imprinting and fetal overgrowth. Dams were treated during pregnancy with 1 of 4 methyl sufficient (MS) or methyl deficient (MD) diets, with or without the antibiotic commonly used to deplete folate producing gut microbes. As expected, after ~9 weeks of treatment, dams in MD and MD + antibiotic groups exhibited substantially reduced plasma folate concentrations. H19ICRΔ2,3 mutant lines were more susceptible to adverse pregnancy outcomes caused by methyl deficiency (reduced birth rate and increased pup lethality) and antibiotic (decreased litter size and litter survival). Surprisingly, pup growth/development was only minimally affected by methyl deficiency, while antibiotic treatment caused inverse effects on B6 and H19ICRΔ2,3 lines. B6 pups treated with antibiotic exhibited increased neonatal and weanling bodyweight, while both wildtype and mutant pups of heterozygous H19ICRΔ2,3/+ dams exhibited decreased neonatal bodyweight that persisted into adulthood. Interestingly, only antibiotic-treated pups carrying the H19ICRΔ2,3 mutation exhibited altered DNA methylation at the H19/Igf2 ICR, suggesting ICR epimutation was not sufficient to explain the altered phenotypes. These findings demonstrate that genetic mutation of the H19/Igf2 ICR increases offspring susceptibility to developmental perturbation in the methyl deficiency model, maternal and pup genotype play an essential role, and antibiotic treatment in the model also plays a key independent role.

scholarly journals DNA Methylation as a Future Therapeutic and Diagnostic Target in Rheumatoid Arthritis

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 953 ◽  
Author(s):  
Marzena Ciechomska ◽  
Leszek Roszkowski ◽  
Wlodzimierz Maslinski
Keyword(s):  
Rheumatoid Arthritis ◽  
Dna Methylation ◽  
Joint Destruction ◽  
Synovial Fibroblasts ◽  
Genetic Mutation ◽  
Unknown Etiology ◽  
Non Invasive ◽  
Fibroblast Like Synoviocytes

Rheumatoid arthritis (RA) is a long-term autoimmune disease of unknown etiology that leads to progressive joint destruction and ultimately to disability. RA affects as much as 1% of the population worldwide. To date, RA is not a curable disease, and the mechanisms responsible for RA development have not yet been well understood. The development of more effective treatments and improvements in the early diagnosis of RA is direly needed to increase patients’ functional capacity and their quality of life. As opposed to genetic mutation, epigenetic changes, such as DNA methylation, are reversible, making them good therapeutic candidates, modulating the immune response or aggressive synovial fibroblasts (FLS—fibroblast-like synoviocytes) activity when it is necessary. It has been suggested that DNA methylation might contribute to RA development, however, with insufficient and conflicting results. Besides, recent studies have shown that circulating cell-free methylated DNA (ccfDNA) in blood offers a very convenient, non-invasive, and repeatable “liquid biopsy”, thus providing a reliable template for assessing molecular markers of various diseases, including RA. Thus, epigenetic therapies controlling autoimmunity and systemic inflammation may find wider implications for the diagnosis and management of RA. In this review, we highlight current challenges associated with the treatment of RA and other autoimmune diseases and discuss how targeting DNA methylation may improve diagnostic, prognostic, and therapeutic approaches.

scholarly journals The Role of Stochasticity in the Origin of Epigenetic Variation in Animal Populations

2020 ◽  
Vol 60 (6) ◽  
pp. 1544-1557 ◽  
Author(s):  
C Biwer ◽  
B Kawam ◽  
V Chapelle ◽  
F Silvestre
Keyword(s):  
Dna Methylation ◽  
Phenotypic Diversity ◽  
Natural Populations ◽  
Genetic Mutation ◽  
Epigenetic Variation ◽  
Epigenetic Variability ◽  
Evolutionary Potential ◽  
Environmental Variance ◽  
Animal Populations

Synopsis Epigenetic mechanisms such as DNA methylation modulate gene expression in a complex fashion are consequently recognized as among the most important contributors to phenotypic variation in natural populations of plants, animals, and microorganisms. Interactions between genetics and epigenetics are multifaceted and epigenetic variation stands at the crossroad between genetic and environmental variance, which make these mechanisms prominent in the processes of adaptive evolution. DNA methylation patterns depend on the genotype and can be reshaped by environmental conditions, while transgenerational epigenetic inheritance has been reported in various species. On the other hand, DNA methylation can influence the genetic mutation rate and directly affect the evolutionary potential of a population. The origin of epigenetic variance can be attributed to genetic, environmental, or stochastic factors. Generally less investigated than the first two components, variation lacking any predictable order is nevertheless present in natural populations and stochastic epigenetic variation, also referred to spontaneous epimutations, can sustain phenotypic diversity. Here, potential sources of such stochastic epigenetic variability in animals are explored, with a focus on DNA methylation. To this day, quantifying the importance of stochasticity in epigenetic variability remains a challenge. However, comparisons between the mutation and the epimutation rates showed a high level of the latter, suggesting a significant role of spontaneous epimutations in adaptation. The implications of stochastic epigenetic variability are multifold: by affecting development and subsequently phenotype, random changes in epigenetic marks may provide additional phenotypic diversity, which can help natural populations when facing fluctuating environments. In isogenic lineages and asexually reproducing organisms, poor or absent genetic diversity can hence be tolerated. Further implication of stochastic epigenetic variability in adaptation is found in bottlenecked invasive species populations and populations using a bet-hedging strategy.

scholarly journals A Comprehensive Sequencing-Based Analysis of Allelic Methylation Patterns in Hemostatic Genes in Human Liver

2019 ◽  
Vol 120 (02) ◽  
pp. 229-242 ◽  
Author(s):  
Martina Olsson Lindvall ◽  
Marcela Davila Lopez ◽  
Sofia Klasson ◽  
Lena Hansson ◽  
Staffan Nilsson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Liver Tissue ◽  
Human Liver ◽  
Genome Wide Association Study ◽  
Warfarin Dose ◽  
Sequencing Data ◽  
Human Liver Tissue ◽  
In Cis ◽  
Hemostatic Genes

AbstractCharacterizing the relationship between genetic, epigenetic (e.g., deoxyribonucleic acid [DNA] methylation), and transcript variation could provide insights into mechanisms regulating hemostasis and potentially identify new drug targets. Several hemostatic factors are synthesized in the liver, yet high-resolution DNA methylation data from human liver tissue is currently lacking for these genes. Single-nucleotide polymorphisms (SNPs) can influence DNA methylation in cis which can affect gene expression. This can be analyzed through allele-specific methylation (ASM) experiments. We performed targeted genomic DNA- and bisulfite-sequencing of 35 hemostatic genes in human liver samples for SNP and DNA methylation analysis, respectively, and integrated the data for ASM determination. ASM-associated SNPs (ASM-SNPs) were tested for association to gene expression in liver using in-house generated ribonucleic acid-sequencing data. We then assessed whether ASM-SNPs associated with gene expression, plasma proteins, or other traits relevant for hemostasis using publicly available data. We identified 112 candidate ASM-SNPs. Of these, 68% were associated with expression of their respective genes in human liver or in other human tissues and 54% were associated with the respective plasma protein levels, activity, or other relevant hemostatic genome-wide association study traits such as venous thromboembolism, coronary artery disease, stroke, and warfarin dose maintenance. Our study provides the first detailed map of the DNA methylation landscape and ASM analysis of hemostatic genes in human liver tissue, and suggests that methylation regulated by genetic variants in cis may provide a mechanistic link between noncoding SNPs and variation observed in circulating hemostatic proteins, prothrombotic diseases, and drug response.

Gestational trophoblastic neoplasia: a meta-analysis evaluating reproductive and obstetrical outcomes after administration of chemotherapy

2019 ◽  
Vol 29 (6) ◽  
pp. 1021-1031 ◽  
Author(s):  
Anastasios Tranoulis ◽  
Dimitra Georgiou ◽  
Ahmad Sayasneh ◽  
John Tidy
Keyword(s):  
General Population ◽  
Pregnancy Outcomes ◽  
Birth Rate ◽  
Meta Analysis ◽  
Live Birth Rate ◽  
Obstetric Outcomes ◽  
Gestational Trophoblastic Neoplasia ◽  
Stillbirth Rate ◽  
Multi Agent ◽  
Adverse Pregnancy

IntroductionGestational trophoblastic neoplasia represents a rare placental malignancy spectrum that is treated with single- or multi-agent chemotherapy. This disease often impacts women of childbearing age, making post-chemotherapy fertility and obstetrical outcomes an important consideration. We aimed to ascertain the pregnancy rates and obstetric outcomes in women with gestational trophoblastic neoplasia after undergoing treatment with chemotherapy.MethodsA systematic literature review was conducted to identify studies that reported post-chemotherapy fertility and obstetric outcomes among women with gestational trophoblastic neoplasia. We performed a single-proportion meta-analysis for the outcomes of conception/pregnancy rate, term live birth rate, first and second trimester spontaneous abortions rate, stillbirth rate, premature delivery rate, and fetal/neonatal malformation rate.ResultsA total of 27 studies were included in the analysis. The median age ranged between 25.5 and 33.1 years. The pregnancy rate among women with a desire to conceive, comprising a total of 1329 women and 1192 pregnancies, was 86.7% (95% CI 80.8% to 91.6%). The term live birth rate in 6752 pregnancies was 75.84% (95% CI 73.4% to 78.2%). The adverse pregnancy outcomes were seemingly comparable to those of the general population apart from a minor increase in the stillbirth rate. The pooled proportion for the outcome of malformation rate was 1.76% (95% CI 1.3% to 2.2%). The repeat mole rate in 6384 pregnancies was 1.28% (95% CI 0.95% to 1.66%). Subsequent sub-group analysis indicated that neither multi-agent chemotherapy nor conception within 12 months post-chemotherapy increased the adverse obstetric events risk or fetal malformations.ConclusionsNearly 90% of patients desiring future fertility after chemotherapy for gestational trophoblastic disease were able to conceive. In addition, adverse pregnancy outcomes were similar to that in the general population. Multi-agent chemotherapy does not seemingly increase the malformation rate.

scholarly journals A Meta-Analysis of Pregnancy Outcomes With Levothyroxine Treatment in Euthyroid Women With Thyroid Autoimmunity

2019 ◽  
Vol 105 (4) ◽  
pp. 1009-1019 ◽  
Author(s):  
Xiaodong Sun ◽  
Ningning Hou ◽  
Hongsheng Wang ◽  
Lin Ma ◽  
Jinhong Sun ◽  
...  
Keyword(s):  
Pregnancy Outcomes ◽  
Birth Rate ◽  
Data Extraction ◽  
Meta Analysis ◽  
Thyroid Autoimmunity ◽  
Data Synthesis ◽  
Definitive Evidence ◽  
Study Selection ◽  
Adverse Pregnancy ◽  
Levothyroxine Treatment

Abstract Context Thyroid autoimmunity (TAI), the most common cause of (sub)clinical hypothyroidism, is associated with adverse pregnancy outcomes. The benefits of levothyroxine (LT4) intervention in women with TAI remain controversial. Objective The purpose of this analysis is to determine the effect of LT4 on pregnancy outcomes in euthyroid women with TAI. Data sources Databases were searched up to May 2019. Study selection Randomized controlled trails (RCTs) and retrospective studies that reported effects of LT4 administration on pregnancy outcomes in euthyroid women with TAI were screened. Data extraction Quality assessment and data extraction were conducted independently by 2 researchers. Conflicts were settled by a third researcher. Data synthesis Six trials comprising 2249 women were included. Overall, no beneficial effect on pregnancy outcomes was observed with LT4 supplementation. For women with individualized initial LT4 dosages, the risk of miscarriage decreased (relative risk [RR] 0.62, 95% CI: 0.41-0.93, I2 = 28%); there was no difference among women with fixed LT4 dosages (RR 0.96, 95% CI: 0.74-1.24, I2 = 0%). Women who initiated LT4 treatment in early pregnancy had a significantly lower preterm birth rate (RR 0.54, 95% CI: 0.31-0.92, I2 = 0%) than those who received no treatment or placebo. No improvement was observed among women who initiated treatment before conception (RR 1.14, 95% CI: 0.71-1.84, I2 = 0%). Conclusion No definitive evidence showed improvement of pregnancy outcomes with LT4 supplementation in euthyroid women with TAI. However, therapeutic strategies, especially dosages and initial times of intervention, may be of great importance. Additional large RCTs are needed in the future.

scholarly journals CLL intraclonal fractions exhibit established and recently acquired patterns of DNA methylation

2020 ◽  
Vol 4 (5) ◽  
pp. 893-905
Author(s):  
Boris A. Bartholdy ◽  
Xiahoua Wang ◽  
Xiao-Jie Yan ◽  
Marién Pascual ◽  
Manxia Fan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Peripheral Blood ◽  
Birth Rate ◽  
Surface Expression ◽  
Lymphocytic Leukemia ◽  
The Other ◽  
Leukemic Cells ◽  
Cell Of Origin ◽  
Mutation Status ◽  
Limited Impact

Abstract Intraclonal subpopulations of circulating chronic lymphocytic leukemia (CLL) cells with different proliferative histories and reciprocal surface expression of CXCR4 and CD5 have been observed in the peripheral blood of CLL patients and named proliferative (PF), intermediate (IF), and resting (RF) cellular fractions. Here, we found that these intraclonal circulating fractions share persistent DNA methylation signatures largely associated with the mutation status of the immunoglobulin heavy chain locus (IGHV) and their origins from distinct stages of differentiation of antigen-experienced B cells. Increased leukemic birth rate, however, showed a very limited impact on DNA methylation of circulating CLL fractions independent of IGHV mutation status. Additionally, DNA methylation heterogeneity increased as leukemic cells advanced from PF to RF in the peripheral blood. This frequently co-occurred with heterochromatin hypomethylation and hypermethylation of Polycomb-repressed regions in the PF, suggesting accumulation of longevity-associated epigenetic features in recently born cells. On the other hand, transcriptional differences between paired intraclonal fractions confirmed their proliferative experience and further supported a linear advancement from PF to RF in the peripheral blood. Several of these differentially expressed genes showed unique associations with clinical outcome not evident in the bulk clone, supporting the pathological and therapeutic relevance of studying intraclonal CLL fractions. We conclude that independent methylation and transcriptional landscapes reflect both preexisting cell-of-origin fingerprints and more recently acquired hallmarks associated with the life cycle of circulating CLL cells.

Promiscuous Cryptic Rearrangements of the MYC Locus Cis-Dysregulate MYC Expression and Are Present in the Majority of Patients with Hyperdiploid Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 724-724
Author(s):  
P Leif Bergsagel ◽  
Maurizio Affer ◽  
Oleg K Glebov ◽  
Wei-Dong D Chen ◽  
Jonathan J Keats ◽  
...  
Keyword(s):  
Gene Expression ◽  
Next Generation Sequencing ◽  
Copy Number ◽  
Genetic Mutation ◽  
Monoallelic Expression ◽  
Next Generation ◽  
Activating Mutations ◽  
Reference Collection ◽  
In Cis ◽  
Generation Sequencing

Abstract Abstract 724 Background: Chromosome content identifies two pathogenic pathways, each occurring in about half of patients with MGUS and multiple myeloma (MM). Hyperdiploid MM (HRD) has 48–75 chromosomes with multiple trisomies selectively involving chromosomes 3, 5, 7, 9, 11, 15, 19 and 21; only 10% of these HRD tumors have primary IgH translocations and no frequent focal genetic mutations have been identified. In contrast primary IgH translocations are identified in over 70% of non-hyperdiploid MM (NHRD). Rearrangements of MYC have been detected by FISH in only 16% of untreated MM, but over 90% of MM cell lines, identifying a late role for MYC in the progression of MM. The introduction of a MYC transgene into a mouse strain predisposed to MGUS results in mice that uniformly develop MM, suggesting a distinct early role of MYC in the progression of MGUS to MM. We report here that rearrangements in a 4Mb region surrounding MYC are present in 70% of HRD, representing the most frequent focal genetic mutation in this genetic subtype of MM. Results: We analyzed the MMRC reference collection of gene expression (Affymetrix Hu133Plus2) and copy number (Agilent 244k CGH) data and performed FISH to identify MYC rearrangements with IgH or IgL loci in 218 patients with untreated and relapsed MM. We found MYC rearrangements in 48% of MM (identified only by FISH in 5%, only by aCGH in 33%, and by both FISH and aCGH in 10%), including 43% of untreated, and 51% of relapsed MM. Using a hyperdiploid index calculated from the median copy number of the chromosomes involved in trisomies we determined that rearrangements of MYC were present in 70% of the top third, 35% of the middle third, and 25% of the bottom third. Using the paired gene expression data we found that the expression of MYC was approximately two-fold higher in the samples with rearrangements compared to those without rearrangements (p<0.001) and about three-fold higher in MM tumors without rearrangements compared to MGUS (p<0001). Using paired RNA and DNA from the MMRC reference collection we determined in 22 informative patients that MYC rearrangements are associated with monoallelic expression of MYC (p<0.01), consistent with cis-dysregulation of MYC. Analysis of the various changes on aCGH, and fine mapping of the genetic architecture of the rearrangements using next generation sequencing identifies a promiscuous array of rearrangements that often result in the introduction of an enhancer within the MYC locus, resulting in its cis-dysregulation. Since they cannot be comprehensively identified by either CGH or FISH alone, more sensitive techniques, such as next generation sequencing approaches, will be required to comprehensively identify all MYC rearrangements in MM. Conclusions: Rearrangements of MYC are the most frequent focal genetic mutation in untreated MM and are particularly prevalent in hyperdiploid MM. While only one third involve an immunoglobulin locus, they all result in cis-dysregulated expression of MYC, and may be one mechanism responsible for the progression of MGUS to MM. Tumors lacking MYC rearrangements bi-allelically over-express MYC by a trans mechanism including potentially inactivating mutations of BLIMP1/PRDM1, or activating mutations of IRF4. We propose two largely non-overlapping pathogenic pathways in MM: HRD associated with frequent MYC rearrangements, and NHRD associated with frequent primary IgH translocations. The prevalence of MYC rearrangements increases with tumor progression, identifying a role for MYC both early and late in tumorigenesis. As therapies that have been reported to target MYC (e.g., IMiDs®, bortezomib, bromodomain inhibitors) are used in the clinic, it will be important to associate their effect with the presence or absence of MYC rearrangements. Disclosures: Bergsagel: Constellation Pharmaceuticals: Consultancy. Keats:Tgen: Employment.

scholarly journals DNA methylation landscapes of 1538 breast cancers reveal a replication-linked clock, epigenomic instability and cis-regulation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rajbir Nath Batra ◽  
Aviezer Lifshitz ◽  
Ana Tufegdzic Vidakovic ◽  
Suet-Feung Chin ◽  
Ankita Sati-Batra ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cpg Island ◽  
Cpg Islands ◽  
Tumor Grade ◽  
Normal Breast ◽  
Breast Cancers ◽  
Reduced Representation ◽  
Reduced Representation Bisulfite Sequencing ◽  
Transcriptional Changes ◽  
In Cis

AbstractDNA methylation is aberrant in cancer, but the dynamics, regulatory role and clinical implications of such epigenetic changes are still poorly understood. Here, reduced representation bisulfite sequencing (RRBS) profiles of 1538 breast tumors and 244 normal breast tissues from the METABRIC cohort are reported, facilitating detailed analysis of DNA methylation within a rich context of genomic, transcriptional, and clinical data. Tumor methylation from immune and stromal signatures are deconvoluted leading to the discovery of a tumor replication-linked clock with genome-wide methylation loss in non-CpG island sites. Unexpectedly, methylation in most tumor CpG islands follows two replication-independent processes of gain (MG) or loss (ML) that we term epigenomic instability. Epigenomic instability is correlated with tumor grade and stage, TP53 mutations and poorer prognosis. After controlling for these global trans-acting trends, as well as for X-linked dosage compensation effects, cis-specific methylation and expression correlations are uncovered at hundreds of promoters and over a thousand distal elements. Some of these targeted known tumor suppressors and oncogenes. In conclusion, this study demonstrates that global epigenetic instability can erode cancer methylomes and expose them to localized methylation aberrations in-cis resulting in transcriptional changes seen in tumors.

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