Browsing by Subject "epigenetics"

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  • Hebbar, Prashantha; Abubaker, Jehad Ahmed; Abu-Farha, Mohamed; Tuomilehto, Jaakko; Al-Mulla, Fahd; Thanaraj, Thangavel Alphonse (2019)
    Despite dedicated nation-wide efforts to raise awareness against the harmful effects of fast-food consumption and sedentary lifestyle, the Arab population continues to struggle with an increased risk for metabolic disorders. Unlike the European population, the Arab population lacks well-established genetic risk determinants for metabolic disorders, and the transferability of established risk loci to this population has not been satisfactorily demonstrated. The most recent findings have identified over 240 genetic risk loci (with similar to 400 independent association signals) for type 2 diabetes, but thus far only 25 risk loci (ADAMTS9, ALX4, BCL11A, CDKAL1, CDKN2A/B, COL8A1, DUSP9, FTO, GCK, GNPDA2, HMG20A, HNF1A, HNF1B, HNF4A, IGF2BP2, JAZF1, KCNJ11 , KCNQ1, MC4R, PPAR gamma, SLC30A8, TCF7L2, TFAP2B, TP53INP1, and WFS1) have been replicated in Arab populations. To our knowledge, large-scale population- or family-based association studies are non-existent in this region. Recently, we conducted genome-wide association studies on Arab individuals from Kuwait to delineate the genetic determinants for quantitative traits associated with anthropometry, lipid profile, insulin resistance, and blood pressure levels. Although these studies led to the identification of novel recessive variants, they failed to reproduce the established loci. However, they provided insights into the genetic architecture of the population, the applicability of genetic models based on recessive mode of inheritance, the presence of genetic signatures of inbreeding due to the practice of consanguinity, and the pleiotropic effects of rare disorders on complex metabolic disorders. This perspective presents analysis strategies and study designs for identifying genetic risk variants associated with diabetes and related traits in Arab populations.
  • Stoddard, Fred; Mäkelä, Pirjo; Puhakainen, Tuula Anneli (INTECHopen, 2011)
  • Xie, Aoji; Ensink, Elizabeth; Li, Peipei; Gordevicius, Juozas; Marshall, Lee L.; George, Sonia; Pospisilik, John Andrew; Aho, Velma T. E.; Houser, Madelyn C.; Pereira, Pedro A. B.; Rudi, Knut; Paulin, Lars; Tansey, Malu G.; Auvinen, Petri; Brundin, Patrik; Brundin, Lena; Labrie, Viviane; Scheperjans, Filip (2022)
    Background The gut microbiome and its metabolites can impact brain health and are altered in Parkinson's disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers. Objectives Here, we investigate whether the changes in the gut microbiome and associated metabolites are related to PD symptoms and epigenetic markers in leucocytes and neurons. Methods Stool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short-chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified genome-wide DNA methylation by targeted bisulfite sequencing. Results We show that lower fecal butyrate and reduced counts of genera Roseburia, Romboutsia, and Prevotella are related to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA regions in PD overlap with those altered in gastrointestinal (GI), autoimmune, and psychiatric diseases. Conclusions Decreased levels of bacterially produced butyrate are related to epigenetic changes in leucocytes and neurons from PD patients and to the severity of their depressive symptoms. PD shares common butyrate-dependent epigenetic changes with certain GI and psychiatric disorders, which could be relevant for their epidemiological relation. (c) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
  • Tobiasson, Magnus; Abdulkadir, Hani; Lennartsson, Andreas; Katayama, Shintaro; Marabita, Francesco; De Paepe, Ayla; Karimi, Mohsen; Krjutskov, Kaarel; Einarsdottir, Elisabet; Grovdal, Michael; Jansson, Monika; Ben Azenkoud, Asmaa; Corddedu, Lina; Lehmann, Soren; Ekwall, Karl; Kere, Juha; Hellstrom-Lindberg, Eva; Ungerstedt, Johanna (2017)
    Azacitidine (Aza) is first-line treatment for patients with high-risk myelodysplastic syndromes (MDS), although its precise mechanism of action is unknown. We performed the first study to globally evaluate the epigenetic effects of Aza on MDS bone marrow progenitor cells assessing gene expression (RNA seq), DNA methylation (Illumina 450k) and the histone modifications H3K18ac and H3K9me3 (ChIP seq). Aza induced a general increase in gene expression with 924 significantly upregulated genes but this increase showed no correlation with changes in DNA methylation or H3K18ac, and only a weak association with changes in H3K9me3. Interestingly, we observed activation of transcripts containing 15 endogenous retroviruses (ERVs) confirming previous cell line studies. DNA methylation decreased moderately in 99% of all genes, with a median beta-value reduction of 0.018; the most pronounced effects seen in heterochromatin. Aza-induced hypomethylation correlated significantly with change in H3K9me3. The pattern of H3K18ac and H3K9me3 displayed large differences between patients and healthy controls without any consistent pattern induced by Aza. We conclude that the marked induction of gene expression only partly could be explained by epigenetic changes, and propose that activation of ERVs may contribute to the clinical effects of Aza in MDS.
  • Garn, Holger; Bahn, Sabine; Baune, Bernhard T.; Binder, Elisabeth B.; Bisgaard, Hans; Chatila, Talal A.; Chavakis, Triantafyllos; Culmsee, Carsten; Dannlowski, Udo; Gay, Steffen; Gern, James; Haahtela, Tari; Kircher, Tilo; Mueller-Ladner, Ulf; Neurath, Markus F.; Preissner, Klaus T.; Reinhardt, Christoph; Rook, Graham; Russell, Shannon; Schmeck, Bernd; Stappenbeck, Thaddeus; Steinhoff, Ulrich; van Os, Jim; Weiss, Scott; Zemlin, Michael; Renz, Harald (2016)
    Recent research indicates that chronic inflammatory diseases, including allergies and autoimmune and neuropsychiatric diseases, share common pathways of cellular and molecular dysregulation. It was the aim of the International von-Behring-Rontgen Symposium (October 16-18, 2014, in Marburg, Germany) to discuss recent developments in this field. These include a concept of biodiversity; the contribution of urbanization, lifestyle factors, and nutrition (eg, vitamin D); and new mechanisms of metabolic and immune dysregulation, such as extracellular and intracellular RNAs and cellular and mitochondrial stress. Epigenetic mechanisms contribute further to altered gene expression and therefore to the development of chronic inflammation. These novel findings provide the foundation for further development of preventive and therapeutic strategies.
  • Acevedo, Nathalie; Scala, Giovanni; Merid, Simon Kebede; Frumento, Paolo; Bruhn, Sören; Andersson, Anna; Ogris, Christoph; Bottai, Matteo; Pershagen, Göran; Koppelman, Gerard H.; Melen, Erik; Sonnhammer, Erik; Alm, Johan; Söderhäll, Cilla; Kere, Juha; Greco, Dario; Scheynius, Annika (2021)
    DNA methylation changes may predispose becoming IgE-sensitized to allergens. We analyzed whether DNA methylation in peripheral blood mononuclear cells (PBMC) is associated with IgE sensitization at 5 years of age (5Y). DNA methylation was measured in 288 PBMC samples from 74 mother/child pairs from the birth cohort ALADDIN (Assessment of Lifestyle and Allergic Disease During INfancy) using the HumanMethylation450BeadChip (Illumina). PBMCs were obtained from the mothers during pregnancy and from their children in cord blood, at 2 years and 5Y. DNA methylation levels at each time point were compared between children with and without IgE sensitization to allergens at 5Y. For replication, CpG sites associated with IgE sensitization in ALADDIN were evaluated in whole blood DNA of 256 children, 4 years old, from the BAMSE (Swedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology) cohort. We found 34 differentially methylated regions (DMRs) associated with IgE sensitization to airborne allergens and 38 DMRs associated with sensitization to food allergens in children at 5Y (Sidak p
  • Dayeh, Tasnim; Tuomi, Tiinamaija; Almgren, Peter; Perfilyev, Alexander; Jansson, Per-Anders; de Mello, Vanessa D.; Pihlajamaki, Jussi; Vaag, Allan; Groop, Leif; Nilsson, Emma; Ling, Charlotte (2016)
    Identification of subjects with a high risk of developing type 2 diabetes (T2D) is fundamental for prevention of the disease. Consequently, it is essential to search for new biomarkers that can improve the prediction of T2D. The aim of this study was to examine whether 5 DNA methylation loci in blood DNA (ABCG1, PHOSPHO1, SOCS3, SREBF1, and TXNIP), recently reported to be associated with T2D, might predict future T2D in subjects from the Botnia prospective study. We also tested if these CpG sites exhibit altered DNA methylation in human pancreatic islets, liver, adipose tissue, and skeletal muscle from diabetic vs. non-diabetic subjects. DNA methylation at the ABCG1 locus cg06500161 in blood DNA was associated with an increased risk for future T2D (OR = 1.09, 95% CI = 1.02-1.16, P-value = 0.007, Q-value = 0.018), while DNA methylation at the PHOSPHO1 locus cg02650017 in blood DNA was associated with a decreased risk for future T2D (OR = 0.85, 95% CI = 0.75-0.95, P-value = 0.006, Q-value = 0.018) after adjustment for age, gender, fasting glucose, and family relation. Furthermore, the level of DNA methylation at the ABCG1 locus cg06500161 in blood DNA correlated positively with BMI, HbA1c, fasting insulin, and triglyceride levels, and was increased in adipose tissue and blood from the diabetic twin among monozygotic twin pairs discordant for T2D. DNA methylation at the PHOSPHO1 locus cg02650017 in blood correlated positively with HDL levels, and was decreased in skeletal muscle from diabetic vs. non-diabetic monozygotic twins. DNA methylation of cg18181703 (SOCS3), cg11024682 (SREBF1), and cg19693031 (TXNIP) was not associated with future T2D risk in subjects from the Botnia prospective study.
  • Krali, Olga; Palle, Josefine; Backlin, Christofer L.; Abrahamsson, Jonas; Noren-Nyström, Ulrika; Hasle, Henrik; Jahnukainen, Kirsi; Jónsson, Olafur Gisli; Hovland, Randi; Lausen, Birgitte; Larsson, Rolf; Palmqvist, Lars; Staffas, Anna; Zeller, Bernward; Nordlund, Jessica (2021)
    Pediatric acute myeloid leukemia (AML) is a heterogeneous disease composed of clinically relevant subtypes defined by recurrent cytogenetic aberrations. The majority of the aberrations used in risk grouping for treatment decisions are extensively studied, but still a large proportion of pediatric AML patients remain cytogenetically undefined and would therefore benefit from additional molecular investigation. As aberrant epigenetic regulation has been widely observed during leukemogenesis, we hypothesized that DNA methylation signatures could be used to predict molecular subtypes and identify signatures with prognostic impact in AML. To study genome-wide DNA methylation, we analyzed 123 diagnostic and 19 relapse AML samples on Illumina 450k DNA methylation arrays. We designed and validated DNA methylation-based classifiers for AML cytogenetic subtype, resulting in an overall test accuracy of 91%. Furthermore, we identified methylation signatures associated with outcome in t(8;21)/RUNX1-RUNX1T1, normal karyotype, and MLL/KMT2A-rearranged subgroups (p < 0.01). Overall, these results further underscore the clinical value of DNA methylation analysis in AML.
  • Nordlund, Jessica; Backlin, Christofer L.; Zachariadis, Vasilios; Cavelier, Lucia; Dahlberg, Johan; Ofverholm, Ingegerd; Barbany, Gisela; Nordgren, Ann; Overnas, Elin; Abrahamsson, Jonas; Flaegstad, Trond; Heyman, Mats M.; Jonsson, Olafur G.; Kanerva, Jukka; Larsson, Rolf; Palle, Josefine; Schmiegelow, Kjeld; Gustafsson, Mats G.; Lonnerholm, Gudmar; Forestier, Erik; Syvanen, Ann-Christine (2015)
  • van der Vossen, Eduard W. J.; Bastos, Diogo; Stols-Goncalves, Daniela; de Goffau, Marcus C.; Davids, Mark; Pereira, Joao P. B.; Li Yim, Andrew Y. F.; Henneman, Peter; Netea, Mihai G.; de Vos, Willem M.; de Jonge, Wouter; Groen, Albert K.; Nieuwdorp, Max; Levin, Evgeni (2021)
    Accumulating evidence shows that microbes with their theater of activity residing within the human intestinal tract (i.e., the gut microbiome) influence host metabolism. Some of the strongest results come from recent fecal microbial transplant (FMT) studies that relate changes in intestinal microbiota to various markers of metabolism as well as the pathophysiology of insulin resistance. Despite these developments, there is still a limited understanding of the multitude of effects associated with FMT on the general physiology of the host, beyond changes in gut microbiome composition. We examined the effect of either allogenic (lean donor) or autologous FMTs on the gut microbiome, plasma metabolome, and epigenomic (DNA methylation) reprogramming in peripheral blood mononuclear cells in individuals with metabolic syndrome measured at baseline (pre-FMT) and after 6 weeks (post-FMT). Insulin sensitivity was determined with a stable isotope-based 2 step hyperinsulinemic clamp and multivariate machine learning methodology was used to uncover discriminative microbes, metabolites, and DNA methylation loci. A larger gut microbiota shift was associated with an allogenic than with autologous FMT. Furthemore, the data results of the the allogenic FMT group data indicates that the introduction of new species can potentially modulate the plasma metabolome and (as a result) the epigenome. Most notably, the introduction of Prevotella ASVs directly correlated with methylation of AFAP1, a gene involved in mitochondrial function, insulin sensitivity, and peripheral insulin resistance (Rd, rate of glucose disappearance). FMT was found to have notable effects on the gut microbiome but also on the host plasma metabolome and the epigenome of immune cells providing new avenues of inquiry in the context of metabolic syndrome treatment for the manipulation of host physiology to achieve improved insulin sensitivity.
  • Kere, Maura; Gruzieva, Olena; Ullemar, Vilhelmina; Söderhäll, Cilla; Greco, Dario; Kull, Inger; Bergström, Anna; Pershagen, Göran; Almqvist, Catarina; Melén, Erik (2020)
  • Int Headache Genetics Consortium (2018)
    Background The biological mechanisms of headache chronification are poorly understood. We aimed to identify changes in DNA methylation associated with the transformation from episodic to chronic headache. Methods Participants were recruited from the population-based Norwegian HUNT Study. Thirty-six female headache patients who transformed from episodic to chronic headache between baseline and follow-up 11 years later were matched against 35 controls with episodic headache. DNA methylation was quantified at 485,000 CpG sites, and changes in methylation level at these sites were compared between cases and controls by linear regression analysis. Data were analyzed in two stages (Stages 1 and 2) and in a combined meta-analysis. Results None of the top 20 CpG sites identified in Stage 1 replicated in Stage 2 after multiple testing correction. In the combined meta-analysis the strongest associated CpG sites were related to SH2D5 and NPTX2, two brain-expressed genes involved in the regulation of synaptic plasticity. Functional enrichment analysis pointed to processes including calcium ion binding and estrogen receptor pathways. Conclusion In this first genome-wide study of DNA methylation in headache chronification several potentially implicated loci and processes were identified. The study exemplifies the use of prospectively collected population cohorts to search for epigenetic mechanisms of disease.
  • elDandashi, Rahaf (Helsingin yliopisto, 2021)
    Epigenetics is the study of changes in gene function without affecting the DNA sequence. Epigenetics studies the effects of the environment and behavior on the genome. Researchers have been able to detect several epigenetic modifications such as –DNA methylation, histone acetylation, and microRNA-associated gene silencing. Changes in the epigenome are essential for proper cell function and normal development and can also be induced by environmental factors. Stress is defined as a biological response to physiological and psychological demands which can affect cellular homeostasis. Factors such as prenatal life stress can affect gene function without directly altering the DNA nucleotide sequence. Elevated levels of stress can immobilize with the ability to impair cognitive function. There is evidence that suggests the involvement of epigenetic regulation in disorders such as addiction, depression, schizophrenia, and cognitive dysfunction. Therefore, this systematic review discusses recent findings of the role of epigenetics in prenatal exposure to stress. To achieve this, the thesis will cover different subtopics from genetics, neurobiology, and diseases, neuroscience, biological psychiatry, life sciences, medicine, behavioral brain research, biochemistry & molecular biology, as well as neuroendocrinology. Research questions are 1) Is there an association between epigenetics and prenatal stress? 2) What kind of mechanisms have been found? 3) What kind of techniques have been used in the identification of potential epigenetic mechanisms? What genes are associated with these epigenetic changes?. This study followed the "The Preferred Reporting Items for Systematic Reviews and Meta-Analyses" (PRISMA) guideline checklist. Eligibility criteria and search terms where be selected and documented to offer the widest range of articles covering the subjects of this study. A literature search was done using PubMed/Medline, Google scholar, and gray literature. The last sample comprised 59 articles. Data were extracted so that the participants, intervention, comparisons, and outcomes were included. The literature search conducted in this systematic review identified a few findings. First is that the majority of animal and human studies found a significant or moderate association between epigenetics and prenatal stress. Second, DNA methylation is the most studied epigenetic mechanism in maternal exposure to stress Third, genome-wide studies were more common in human studies than in animals and the most widely used method used is Infinium HumanMethylation450 Bead Chip. However, the common methods used in human and animal studies are most likely because of the small sample size and causation cannot be determined. Finally, NR3C1 and FKBP5 genes were the most studied in human studies where they showed the strongest association between prenatal stress and epigenetic modifications. While in animal studies, the most studied genes were Bdnf and Dnmt1 as they showed a significant methylation level after maternal prenatal stress exposure. In conclusion, maternal prenatal stress could trigger epigenetic alterations in neonates in both animals and humans. This holistic review detailed and evaluated locus-specific and studies exploring current knowledge about associations between maternal prenatal stress and epigenetic changes.
  • Zannas, Anthony S.; Jia, Meiwen; Hafner, Kathrin; Baumert, Jens; Wiechmann, Tobias; Pape, Julius C.; Arloth, Janine; Ködel, Maik; Martinelli, Silvia; Roitman, Maria; Roeh, Simone; Haehle, Andreas; Emeny, Rebecca T.; Iurato, Stella; Carrillo-Roa, Tania; Lahti, Jari; Räikkönen, Katri; Eriksson, Johan G.; Drake, Amanda J.; Waldenberger, Melanie; Wahl, Simone; Kunze, Sonja; Lucae, Susanne; Bradley, Bekh; Gieger, Christian; Hausch, Felix; Smith, Alicia K.; Ressler, Kerry J.; Mueller-Myhsok, Bertram; Ladwig, Karl-Heinz; Rein, Theo; Gassen, Nils C.; Binder, Elisabeth B. (2019)
    Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n > 3,000), aging synergized with stress-related phenotypes, measured with childhood trauma and major depression questionnaires, to epigenetically up-regulate FKBP5 expression. These age/stress-related epigenetic effects were recapitulated in a cellular model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher FKBP5 mRNA with a proinflammatory profile and altered NF-kappa B-related gene networks. Accordingly, experiments in immune cells showed that higher FKBP5 promotes inflammation by strengthening the interactions of NF-kappa B regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-kappa B. Further, the age/stress-related epigenetic signature enhanced FKBP5 response to NF-kappa B through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that aging/stress-driven FKBP5-NF-kappa B signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.
  • Cazaly, Emma; Saad, Joseph; Wang, Wenyu; Heckman, Caroline; Ollikainen, Miina; Tang, Jing (2019)
    Epigenetic research involves examining the mitotically heritable processes that regulate gene expression, independent of changes in the DNA sequence. Recent technical advances such as whole-genome bisulfite sequencing and affordable epigenomic array-based technologies, allow researchers to measure epigenetic profiles of large cohorts at a genome-wide level, generating comprehensive high-dimensional datasets that may contain important information for disease development and treatment opportunities. The epigenomic profile for a certain disease is often a result of the complex interplay between multiple genetic and environmental factors, which poses an enormous challenge to visualize and interpret these data. Furthermore, due to the dynamic nature of the epigenome, it is critical to determine causal relationships from the many correlated associations. In this review we provide an overview of recent data analysis approaches to integrate various omics layers to understand epigenetic mechanisms of complex diseases, such as obesity and cancer. We discuss the following topics: (i) advantages and limitations of major epigenetic profiling techniques, (ii) resources for standardization, annotation and harmonization of epigenetic data, and (iii) statistical methods and machine learning methods for establishing data-driven hypotheses of key regulatory mechanisms. Finally, we discuss the future directions for data integration that shall facilitate the discovery of epigenetic-based biomarkers and therapies.
  • Xu, Hongen; Pausch, Hubert; Venhoranta, Heli; Rutkowska, Karolina; Wurmser, Christine; Rieblinger, Beate; Flisikowska, Tatiana; Frishman, Dmitrij; Zwierzchowski, Lech; Fries, Ruedi; Andersson, Magnus; Kind, Alexander; Schnieke, Angelika; Flisikowski, Krzysztof (2017)
    Intrauterine growth restriction (IUGR) is caused by dysregulation of placental metabolism. Paternally inherited IUGR mutations in the fetus influence maternal physiology via the placenta. However, it is not known whether the maternal placenta also affects the extent of IUGR in such fetuses. In cattle and other ruminants, maternal-fetal communication occurs primarily at the placentomes. We previously identified a 3 deletion in the noncoding MER1 repeat containing imprinted transcript 1 (MIMT1) gene that, when inherited from the sire, causes IUGR and late abortion in Ayshire cattle with variable levels of severity. Here, we compared the transcriptome and genomic imprinting in fetal and maternal placentome components of wild-type and MIMT1(Del/WT) fetuses before IUGR became apparent, to identify key early events. Transcriptome analysis revealed fewer differentially expressed genes in maternal than fetal MIMT1(Del/WT) placentome. AST1, within the PEG3 domain, was the only gene consistently reduced in IUGR in both fetal and maternal samples. Several genes showed an imprinting pattern associated with IUGR, of which only secernin 3 (SCRN3) and paternally expressed 3 (PEG3) were differentially imprinted in both placentome components. Loss of strictly monoallelic, allele-specific expression (similar to 80:20) of PEG3 in the maternal MIMT1(Del/WT) placenta could be associated with incomplete penetrance of MIMT1(Del). Our data show that dysregulation of the PEG3 domain is involved in IUGR, but also reveal that maternal placental tissues may affect the penetrance of the paternally inherited IUGR mutation.
  • Maciel, Izaque de Sousa; Sales, Amanda J.; Casarotto, Plinio C.; Castrén, Eero; Biojone, Caroline; Joca, Samia R. L. (2022)
    It has been postulated that the activation of NMDA receptors (NMDAr) and nitric oxide (NO) production in the hippocampus is involved in the behavioral consequences of stress. Stress triggers NMDAr-induced calcium influx in limbic areas, such as the hippocampus, which in turn activates neuronal NO synthase (nNOS). Inhibition of nNOS or NMDAr activity can prevent stress-induced effects in animal models, but the molecular mechanisms behind this effect are still unclear. In this study, cultured hippocampal neurons treated with NMDA or dexamethasone showed an increased of DNA methyltransferase 3b (DNMT3b) mRNA expression, which was blocked by pre-treatment with nNOS inhibitor n(omega)-propyl-l-arginine (NPA). In rats submitted to the Learned Helplessness paradigm (LH), we observed that inescapable stress increased DNMT3b mRNA expression at 1h and 24h in the hippocampus. The NOS inhibitors 7-NI and aminoguanidine (AMG) decreased the number of escape failures in LH and counteracted the changes in hippocampal DNMT3b mRNA induced in this behavioral paradigm. Altogether, our data suggest that NO produced in response to NMDAr activation following stress upregulates DNMT3b in the hippocampus.
  • Olkkonen, Emmi (Helsingin yliopisto, 2021)
    Long non-coding RNAs (lncRNAs) are over 200 bp long RNA molecules that are not translated into protein. LncRNAs can regulate the expression of protein coding genes, and studies have indicated their role in stress response. Stress response has also been associated with differences in the structure of the myelin sheaths in the mouse brain cortex. Myelin is produced by mature oligodendrocytes (OLGs), and therefore, OLGs are likely to play a role in stress response. The aim of this thesis was to find lncRNAs differentially expressed in the oligodendrocytes and myelin on the medial prefrontal cortex of stressed mice in comparison to controls. Mice of strains C57/6NCrl and DBA/2NCrl, differing in stress response, were exposed to chronic social defeat stress. After the stress paradigm, the mice were assigned as stress-susceptible or stress-resilient, the susceptible mice exhibiting anxiety-like behavior. RNA from OLGs and myelin from the medial prefrontal cortex of the mice was sequenced, and I compared the lncRNA expression levels between stressed and control mice and stress-susceptible and resilient mice using bioinformatic methods. I also assessed modules formed by lncRNAs and protein coding genes correlating in expression in both datasets. I used RT-qPCR to investigate if results from two differentially expressed lncRNAs, Gm37885 and Neat1, replicate in a stress hormone-treated oligodendrocyte cell line. Three hundred and seventy lncRNAs were differentially expressed between stressed mice and controls or stress-susceptible and resilient mice in the OLG dataset and 132 in the myelin dataset. Two hundred and 87 of them overlapped with a protein coding gene in the OLG and myelin datasets, respectively. Sixty-one percent of the differentially expressed lncRNAs were specific to comparisons in the OLG dataset and 73 % in the myelin dataset, but 39 % of the differentially expressed lncRNAs in the OLG dataset and 27 % in the myelin dataset were shared between them. No module of genes with correlating expression levels was associated with stress, but the expression levels of two correlation modules from each dataset differed between strains. The results for one of the differentially expressed lncRNAs, Gm37885, replicated in stressed Oli-neu cells in RT-qPCR. The results of my thesis indicate that multiple lncRNAs are involved in the mouse stress response, as many were differentially expressed and shared between phenotype comparisons. Additionally, significant gene expression differences were observed between strains, which could contribute to the previously reported strain differences in stress susceptibility. The results also suggest a specific role of Gm37885 in GR-mediated stress response. However, the function of Gm37885 remains unknown, and further studies regarding Gm37885 and the other differentially expressed lncRNAs should be carried out to draw conclusions of their contribution to the OLG-mediated stress response.
  • Viitaniemi, Heidi M.; Verhagen, Irene; Visser, Marcel E.; Honkela, Antti; van Oers, Kees; Husby, Arild (2019)
    In seasonal environments, timing of reproduction is a trait with important fitness consequences, but we know little about the molecular mechanisms that underlie the variation in this trait. Recently, several studies put forward DNA methylation as a mechanism regulating seasonal timing of reproduction in both plants and animals. To understand the involvement of DNA methylation in seasonal timing of reproduction, it is necessary to examine within-individual temporal changes in DNA methylation, but such studies are very rare. Here, we use a temporal sampling approach to examine changes in DNA methylation throughout the breeding season in female great tits (Parus major) that were artificially selected for early timing of breeding. These females were housed in climate-controlled aviaries and subjected to two contrasting temperature treatments. Reduced representation bisulfite sequencing on red blood cell derived DNA showed genome-wide temporal changes in more than 40,000 out of the 522,643 CpG sites examined. Although most of these changes were relatively small (mean within-individual change of 6%), the sites that showed a temporal and treatment-specific response in DNA methylation are candidate sites of interest for future studies trying to understand the link between DNA methylation patterns and timing of reproduction.
  • Ramakrishnan, Muthusamy; Satish, Lakkakula; Kalendar, Ruslan; Mathiyazhagan, Narayanan; Sabariswaran, Kandasamy; Sharma, Anket; Emamverdian, Abolghassem; Wei, Qiang; Zhou, Mingbing (2021)
    Plant development processes are regulated by epigenetic alterations that shape nuclear structure, gene expression, and phenotypic plasticity; these alterations can provide the plant with protection from environmental stresses. During plant growth and development, these processes play a significant role in regulating gene expression to remodel chromatin structure. These epigenetic alterations are mainly regulated by transposable elements (TEs) whose abundance in plant genomes results in their interaction with genomes. Thus, TEs are the main source of epigenetic changes and form a substantial part of the plant genome. Furthermore, TEs can be activated under stress conditions, and activated elements cause mutagenic effects and substantial genetic variability. This introduces novel gene functions and structural variation in the insertion sites and primarily contributes to epigenetic modifications. Altogether, these modifications indirectly or directly provide the ability to withstand environmental stresses. In recent years, many studies have shown that TE methylation plays a major role in the evolution of the plant genome through epigenetic process that regulate gene imprinting, thereby upholding genome stability. The induced genetic rearrangements and insertions of mobile genetic elements in regions of active euchromatin contribute to genome alteration, leading to genomic stress. These TE-mediated epigenetic modifications lead to phenotypic diversity, genetic variation, and environmental stress tolerance. Thus, TE methylation is essential for plant evolution and stress adaptation, and TEs hold a relevant military position in the plant genome. High-throughput techniques have greatly advanced the understanding of TE-mediated gene expression and its associations with genome methylation and suggest that controlled mobilization of TEs could be used for crop breeding. However, development application in this area has been limited, and an integrated view of TE function and subsequent processes is lacking. In this review, we explore the enormous diversity and likely functions of the TE repertoire in adaptive evolution and discuss some recent examples of how TEs impact gene expression in plant development and stress adaptation.