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Mutations in the enzyme isocitrate dehydrogenase 1 (IDH1) lead to metabolic alterations and a sustained formation of 2-hydroxyglutarate (2-HG). 2-HG is an oncometabolite as it inhibits the activity of alpha-ketoglutarate-dependent dioxygenases such as ten-eleven translocation (TET) enzymes. Inhibitors of mutant IDH enzymes, like ML309, are currently tested in order to lower the levels of 2-HG. Vitamin C (VC) is an inducer of TET enzymes. To test a new therapeutic avenue of synergistic effects, the anti-neoplastic activity of inhibition of mutant IDH1 via ML309 in the presence of VC was investigated in the colon cancer cell line HCT116 IDH1(R132H/+) (harbouring a mutated IDH1 allele) and the parental cells HCT116 IDH1(+/+) (wild type IDH1). Measurement of the oncometabolite indicated a 56-fold higher content of 2-HG in mutated cells compared to wild type cells. A significant reduction of 2-HG was observed in mutated cells after treatment with ML 309, whereas VC produced only minimally changes of the oncometabolite. However, combinatorial treatment with both, ML309 and VC, in mutated cells induced pronounced reduction of 2-HG leading to levels comparable to those in wild type cells. The decreased level of 2-HG in mutated cells after combinatorial treatment was accompanied by an enhanced global DNA hydroxymethylation and an increased gene expression of certain tumour suppressors. Moreover, mutated cells showed an increased percentage of apoptotic cells after treatment with non-cytotoxic concentrations of ML309 and VC. These results suggest that combinatorial therapy is of interest for further investigation to rescue TET activity and treatment of IDH1/2 mutated cancers.
The increasing introduction of non-native plant species may pose a threat to local biodiversity. However, the basis of successful plant invasion is not conclusively understood, especially since these plant species can adapt to the new range within a short period of time despite impoverished genetic diversity of the starting populations. In this context, DNA methylation is considered promising to explain successful adaptation mechanisms in the new habitat. DNA methylation is a heritable variation in gene expression without changing the underlying genetic information. Thus, DNA methylation is considered a so-called epigenetic mechanism, but has been studied in mainly clonally reproducing plant species or genetic model plants. An understanding of this epigenetic mechanism in the context of non-native, predominantly sexually reproducing plant species might help to expand knowledge in biodiversity research on the interaction between plants and their habitats and, based on this, may enable more precise measures in conservation biology.
For my studies, I combined chemical DNA demethylation of field-collected seed material from predominantly sexually reproducing species and rearing offsping under common climatic conditions to examine DNA methylation in an ecological-evolutionary context. The contrast of chemically treated (demethylated) plants, whose variation in DNA methylation was artificially reduced, and untreated control plants of the same species allowed me to study the impact of this mechanism on adaptive trait differentiation and local adaptation. With this experimental background, I conducted three studies examining the effect of DNA methylation in non-native species along a climatic gradient and also between climatically divergent regions.
The first study focused on adaptive trait differentiation in two invasive perennial goldenrod species, Solidago canadensis sensu latu and S. gigantea AITON, along a climate gradient of more than 1000 km in length in Central Europe. I found population differences in flowering timing, plant height, and biomass in the temporally longer-established S. canadensis, but only in the number of regrowing shoots for S. gigantea. While S. canadensis did not show any population structure, I was able to identify three genetic groups along this climatic gradient in S. gigantea. Surprisingly, demethylated plants of both species showed no change in the majority of traits studied. In the subsequent second study, I focused on the longer-established goldenrod species S. canadensis and used molecular analyses to infer spatial epigenetic and genetic population differences in the same specimens from the previous study. I found weak genetic but no epigenetic spatial variation between populations. Additionally, I was able to identify one genetic marker and one epigenetic marker putatively susceptible to selection. However, the results of this study reconfirmed that the epigenetic mechanism of DNA methylation appears to be hardly involved in adaptive processes within the new range in S. canadensis.
Finally, I conducted a third study in which I reciprocally transplanted short-lived plant species between two climatically divergent regions in Germany to investigate local adaptation at the plant family level. For this purpose, I used four plant families (Amaranthaceae, Asteraceae, Plantaginaceae, Solanaceae) and here I additionally compared between non-native and native plant species. Seeds were transplanted to regions with a distance of more than 600 kilometers and had either a temperate-oceanic or a temperate-continental climate. In this study, some species were found to be maladapted to their own local conditions, both in non-native and native plant species alike. In demethylated individuals of the plant species studied, DNA methylation had inconsistent but species-specific effects on survival and biomass production. The results of this study highlight that DNA methylation did not make a substantial contribution to local adaptation in the non-native as well as native species studied.
In summary, my work showed that DNA methylation plays a negligible role in both adaptive trait variation along climatic gradients and local adaptation in non-native plant species that either exhibit a high degree of genetic variation or rely mainly on sexual reproduction with low clonal propagation. I was able to show that the adaptive success of these non-native plant species can hardly be explained by DNA methylation, but could be a possible consequence of multiple introductions, dispersal corridors and meta-population dynamics. Similarly, my results illustrate that the use of plant species that do not predominantly reproduce clonally and are not model plants is essential to characterize the effect size of epigenetic mechanisms in an ecological-evolutionary context.
The development of type 2 diabetes (T2D) is driven by genetic as well as life style factors. However, even genetically identical female NZO mice on a high-fat diet show a broad variation in T2D onset. The main objective of this study was to elucidate and investigate early epigenetic determinants of type 2 diabetes. Prior to other experiments, early fat content of the liver (<55.2 HU) in combination with blood glucose concentrations (>8.8 mM) were evaluated as best predictors of diabetes in NZO females. Then, DNA methylome and transcriptome were profiled to identify molecular pathophysiological changes in the liver before diabetes onset. The major finding of this thesis is that alterations in the hepatic DNA methylome precede diabetes onset. Of particular interest were 702 differentially methylated regions (DMRs), of which 506 DMRs had genic localization. These inter-individual DMRs were enriched by fivefold in the KEGG pathway type 2 diabetes mellitus, independent of the level of gene expression, demonstrating an epigenetic predisposition toward diabetes. Interestingly, among the list of hepatic DMRs, eleven DMRs were associated with known imprinted genes in the mouse genome. Thereby, six DMRs (Nap1l5, Mest, Plagl1, Gnas, Grb10 and Slc38a4) localized to imprinting control regions, including five iDMRs that exhibited hypermethylation in livers of diabetes-prone mice. This suggests that gain of DNA methylation in multiple loci of the paternal alleles has unfavourable metabolic consequences for the offspring. Further, the comparative liver transcriptome analysis demonstrated differences in expression levels of 1492 genes related to metabolically relevant pathways, such as citrate cycle and fatty acid metabolism. The integration of hepatic transcriptome and DNA methylome indicated that 449 differentially expressed genes were potentially regulated by DNA methylation, including genes implicated in insulin signaling. In addition, liver transcriptomic profiling of diabetes-resistant and diabetes-prone mice revealed a potential transcriptional dysregulation of 17 hepatokines, in particular Hamp. The hepatic expression of Hamp was decreased by 52% in diabetes-prone mice, on account of an increase in DNA methylation of promoter CpG-118. Hence, HAMP protein levels were lower in mice prone to develop diabetes, which correlated to higher liver triglyceride levels.. In sum, the identified DNA methylation changes appear to collectively favor the initiation and progression of diabetes in female NZO mice. In near future, epigenetic biomarkers are likely to contribute to improved diagnosis for T2D.
Many invasive species have rapidly adapted to different environments in their new ranges. This is surprising, as colonization is usually associated with reduced genetic variation. Heritable phenotypic variation with an epigenetic basis may explain this paradox. Here, we assessed the contribution of DNA methylation to local adaptation in native and naturalized non-native ruderal plant species in Germany. We reciprocally transplanted offspring from natural populations of seven native and five non-native plant species between the Konstanz region in the south and the Potsdam region in the north of Germany. Before the transplant, half of the seeds were treated with the demethylation agent zebularine. We recorded survival, flowering probability, and biomass production as fitness estimates. Contrary to our expectations, we found little evidence for local adaptation, both among the native and among the non-native plant species. Zebularine treatment had mostly negative effects on overall plant performance, regardless of whether plants were local or not, and regardless of whether they were native or non-native. Synthesis. We conclude that local adaptation, at least at the scale of our study, plays no major role in the success of non-native and native ruderal plants. Consequently, we found no evidence yet for an epigenetic basis of local adaptation.
Low birth weight (LBW) is associated with diseases in adulthood. The birthweight attributed risk is independent of confounding such as gestational age, sex of the newborn but also social factors. The birthweight attributed risk for diseases in later life holds for the whole spectrum of birthweight. This raises the question what pathophysiological principle is actually behind the association. In this review, we provide evidence that LBW is a surrogate of insulin resistance. Insulin resistance has been identified as a key factor leading to type 2 diabetes, cardiovascular disease as well as kidney diseases. We first provide evidence linking LBW to insulin resistance during intrauterine life. This might be caused by both genetic (genetic variations of genes controlling glucose homeostasis) and/or environmental factors (due to alterations of macronutrition and micronutrition of the mother during pregnancy, but also effects of paternal nutrition prior to conception) leading via epigenetic modifications to early life insulin resistance and alterations of intrauterine growth, as insulin is a growth factor in early life. LBW is rather a surrogate of insulin resistance in early life - either due to inborn genetic or environmental reasons - rather than a player on its own.
In June 2019, more than a hundred plant researchers met in Cologne, Germany, for the 6th European Workshop on Plant Chromatin (EWPC). This conference brought together a highly dynamic community of researchers with the common aim to understand how chromatin organization controls gene expression, development, and plant responses to the environment. New evidence showing how epigenetic states are set, perpetuated, and inherited were presented, and novel data related to the three-dimensional organization of chromatin within the nucleus were discussed. At the level of the nucleosome, its composition by different histone variants and their specialized histone deposition complexes were addressed as well as the mechanisms involved in histone post-translational modifications and their role in gene expression. The keynote lecture on plant DNA methylation by Julie Law (SALK Institute) and the tribute session to Lars Hennig, honoring the memory of one of the founders of the EWPC who contributed to promote the plant chromatin and epigenetic field in Europe, added a very special note to this gathering. In this perspective article we summarize some of the most outstanding data and advances on plant chromatin research presented at this workshop.
In June 2019, more than a hundred plant researchers met in Cologne, Germany, for the 6th European Workshop on Plant Chromatin (EWPC). This conference brought together a highly dynamic community of researchers with the common aim to understand how chromatin organization controls gene expression, development, and plant responses to the environment. New evidence showing how epigenetic states are set, perpetuated, and inherited were presented, and novel data related to the three-dimensional organization of chromatin within the nucleus were discussed. At the level of the nucleosome, its composition by different histone variants and their specialized histone deposition complexes were addressed as well as the mechanisms involved in histone post-translational modifications and their role in gene expression. The keynote lecture on plant DNA methylation by Julie Law (SALK Institute) and the tribute session to Lars Hennig, honoring the memory of one of the founders of the EWPC who contributed to promote the plant chromatin and epigenetic field in Europe, added a very special note to this gathering. In this perspective article we summarize some of the most outstanding data and advances on plant chromatin research presented at this workshop.
Background: Hepatic steatosis is a common chronic liver disease that can progress into more severe stages of NAFLD or promote the development of life-threatening secondary diseases for some of those affected. These include the liver itself (nonalcoholic steatohepatitis or NASH; fibrosis and cirrhosis, and hepatocellular carcinoma) or other organs such as the vessels and the heart (cardiovascular disease) or the islets of Langerhans (type 2 diabetes). In addition to elevated caloric intake and a sedentary lifestyle, genetic and epigenetic predisposition contribute to the development of NAFLD and the secondary diseases. Scope of review: We present data from genome-wide association studies (GWAS) and functional studies in rodents which describe polymorphisms identified in genes relevant for the disease as well as changes caused by altered DNA methylation and gene regulation via specific miRNAs. The review also provides information on the current status of the use of genetic and epigenetic factors as risk markers. Major conclusion: With our overview we provide an insight into the genetic and epigenetic landscape of NAFLD and argue about the applicability of currently defined risk scores for risk stratification and conclude that further efforts are needed to make the scores more usable and meaningful.