TY - GEN A1 - Weyrich, Alexandra A1 - Yasar, Selma A1 - Lenz, Dorina A1 - Fickel, Jörns T1 - Tissue-specific epigenetic inheritance after paternal heat exposure in male wild guinea pigs T2 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - External temperature change has been shown to modify epigenetic patterns, such as DNA methylation, which regulates gene expression. DNA methylation is heritable, and as such provides a mechanism to convey environmental information to subsequent generations. Studies on epigenetic response to temperature increase are still scarce in wild mammals, even more so studies that compare tissue-specific epigenetic responses. Here, we aim to address differential epigenetic responses on a gene and gene pathway level in two organs, liver and testis. We chose these organs, because the liver is the main metabolic and thermoregulation organ, and epigenetic modifications in testis are potentially transmitted to the F2 generation. We focused on the transmission of DNA methylation changes to naive male offspring after paternal exposure to an ambient temperature increase of 10 degrees C, and investigated differential methylated regions of sons sired before and after the paternal exposure using Reduced Representation Bisulfite Sequencing. We detected both a highly tissue-specific epigenetic response, reflected in genes involved in organ-specific metabolic pathways, and a more general regulation of single genes epigenetically modified in both organs. We conclude that genomes are context-specifically differentially epigenetically regulated in response to temperature increase. These findings emphasize the epigenetic relevance in cell differentiation, which is essential for the specific function(s) of complex organs, and is represented in a diverse molecular regulation of genes and gene pathways. The results also emphasize the paternal contribution to adaptive processes. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1431 KW - DNA methylation KW - gene-expression KW - CPG Islands KW - stress KW - hyperthermia KW - testis Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-516525 SN - 1866-8372 IS - 5-6 ER - TY - JOUR A1 - Guerrero, Tania P. A1 - Fickel, Jörns A1 - Benhaiem, Sarah A1 - Weyrich, Alexandra T1 - Epigenomics and gene regulation in mammalian social systems JF - Current zoology N2 - Social epigenomics is a new field of research that studies how the social environment shapes the epigenome and how in turn the epigenome modulates behavior. We focus on describing known gene-environment interactions (GEIs) and epigenetic mechanisms in different mammalian social systems. To illustrate how epigenetic mechanisms integrate GEls, we highlight examples where epigenetic mechanisms are associated with social behaviors and with their maintenance through neuroendocrine, locomotor, and metabolic responses. We discuss future research trajectories and open questions for the emerging field of social epigenomics in nonmodel and naturally occurring social systems. Finally, we outline the technological advances that aid the study of epigenetic mechanisms in the establishment of GEIs and vice versa. KW - epigenetics KW - DNA methylation KW - histone modification KW - rank KW - social status KW - social systems Y1 - 2020 U6 - https://doi.org/10.1093/cz/zoaa005 SN - 1674-5507 SN - 2396-9814 VL - 66 IS - 3 SP - 307 EP - 319 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - Weyrich, Alexandra A1 - Yasar, Selma A1 - Lenz, Dorina A1 - Fickel, Jörns T1 - Tissue-specific epigenetic inheritance after paternal heat exposure in male wild guinea pigs JF - Mammalian genome N2 - External temperature change has been shown to modify epigenetic patterns, such as DNA methylation, which regulates gene expression. DNA methylation is heritable, and as such provides a mechanism to convey environmental information to subsequent generations. Studies on epigenetic response to temperature increase are still scarce in wild mammals, even more so studies that compare tissue-specific epigenetic responses. Here, we aim to address differential epigenetic responses on a gene and gene pathway level in two organs, liver and testis. We chose these organs, because the liver is the main metabolic and thermoregulation organ, and epigenetic modifications in testis are potentially transmitted to the F2 generation. We focused on the transmission of DNA methylation changes to naive male offspring after paternal exposure to an ambient temperature increase of 10 degrees C, and investigated differential methylated regions of sons sired before and after the paternal exposure using Reduced Representation Bisulfite Sequencing. We detected both a highly tissue-specific epigenetic response, reflected in genes involved in organ-specific metabolic pathways, and a more general regulation of single genes epigenetically modified in both organs. We conclude that genomes are context-specifically differentially epigenetically regulated in response to temperature increase. These findings emphasize the epigenetic relevance in cell differentiation, which is essential for the specific function(s) of complex organs, and is represented in a diverse molecular regulation of genes and gene pathways. The results also emphasize the paternal contribution to adaptive processes. KW - DNA methylation KW - gene-expression KW - CPG Islands KW - stress KW - hyperthermia KW - testis Y1 - 2020 U6 - https://doi.org/10.1007/s00335-020-09832-6 SN - 0938-8990 SN - 1432-1777 VL - 31 IS - 5-6 SP - 157 EP - 169 PB - Springer CY - New York ER - TY - JOUR A1 - Witt, Stephanie H. A1 - Frank, Josef A1 - Gilles, Maria A1 - Lang, Maren A1 - Treutlein, Jens A1 - Streit, Fabian A1 - Wolf, Isabell A. C. A1 - Peus, Verena A1 - Scharnholz, Barbara A1 - Send, Tabea S. A1 - Heilmann-Heimbach, Stefanie A1 - Sivalingam, Sugirthan A1 - Dukal, Helene A1 - Strohmaier, Jana A1 - Sütterlin, Marc A1 - Arloth, Janine A1 - Laucht, Manfred A1 - Nöthen, Markus M. A1 - Deuschle, Michael A1 - Rietschel, Marcella T1 - Impact on birth weight of maternal smoking throughout pregnancy mediated by DNA methylation JF - BMC genomics N2 - Background: Cigarette smoking has severe adverse health consequences in adults and in the offspring of mothers who smoke during pregnancy. One of the most widely reported effects of smoking during pregnancy is reduced birth weight which is in turn associated with chronic disease in adulthood. Epigenome-wide association studies have revealed that smokers show a characteristic "smoking methylation pattern", and recent authors have proposed that DNA methylation mediates the impact of maternal smoking on birth weight. The aims of the present study were to replicate previous reports that methylation mediates the effect of maternal smoking on birth weight, and for the first time to investigate whether the observed mediation effects are sex-specific in order to account for known sex-specific differences in methylation levels. Methods: Methylation levels in the cord blood of 313 newborns were determined using the Illumina HumanMethylation450K Beadchip. A total of 5,527 CpG sites selected on the basis of evidence from the literature were tested. To determine whether the observed association between maternal smoking and birth weight was attributable to methylation, mediation analyses were performed for significant CpG sites. Separate analyses were then performed in males and females. Results: Following quality control, 282 newborns eventually remained in the analysis. A total of 25 mothers had smoked consistently throughout the pregnancy. The birthweigt of newborns whose mothers had smoked throughout pregnancy was reduced by >200g. After correction for multiple testing, 30 CpGs showed differential methylation in the maternal smoking subgroup including top "smoking methylation pattern" genes AHRR, MYO1G, GFI1, CYP1A1, and CNTNAP2. The effect of maternal smoking on birth weight was partly mediated by the methylation of cg25325512 (PIM1); cg25949550 (CNTNAP2); and cg08699196 (ITGB7). Sex-specific analyses revealed a mediating effect for cg25949550 (CNTNAP2) in male newborns. Conclusion: The present data replicate previous findings that methylation can mediate the effect of maternal smoking on birth weight. The analysis of sex-dependent mediation effects suggests that the sex of the newborn may have an influence. Larger studies are warranted to investigate the role of both the identified differentially methylated loci and the sex of the newborn in mediating the association between maternal smoking during pregnancy and birth weight. KW - DNA methylation KW - Smoking KW - Birth weight KW - Mediation analysis Y1 - 2018 U6 - https://doi.org/10.1186/s12864-018-4652-7 SN - 1471-2164 VL - 19 PB - BMC CY - London ER - TY - JOUR A1 - Weyrich, Alexandra A1 - Jeschek, Marie A1 - Schrapers, Katharina T. A1 - Lenz, Dorina A1 - Chung, Tzu Hung A1 - Ruebensam, Kathrin A1 - Yasar, Sermin A1 - Schneemann, Markus A1 - Ortmann, Sylvia A1 - Jewgenow, Katarina A1 - Fickel, Jörns T1 - Diet changes alter paternally inherited epigenetic pattern in male Wild guinea pigs JF - Environmental Epigenetics N2 - Epigenetic modifications, of which DNA methylation is the most stable, are a mechanism conveying environmental information to subsequent generations via parental germ lines. The paternal contribution to adaptive processes in the offspring might be crucial, but has been widely neglected in comparison to the maternal one. To address the paternal impact on the offspring’s adaptability to changes in diet composition, we investigated if low protein diet (LPD) in F0 males caused epigenetic alterations in their subsequently sired sons. We therefore fed F0 male Wild guinea pigs with a diet lowered in protein content (LPD) and investigated DNA methylation in sons sired before and after their father’s LPD treatment in both, liver and testis tissues. Our results point to a ‘heritable epigenetic response’ of the sons to the fathers’ dietary change. Because we detected methylation changes also in the testis tissue, they are likely to be transmitted to the F2 generation. Gene-network analyses of differentially methylated genes in liver identified main metabolic pathways indicating a metabolic reprogramming (‘metabolic shift’). Epigenetic mechanisms, allowing an immediate and inherited adaptation may thus be important for the survival of species in the context of a persistently changing environment, such as climate change. KW - DNA methylation KW - exposure KW - wild mammal species KW - inheritance KW - plasticity KW - adaptation Y1 - 2018 U6 - https://doi.org/10.1093/eep/dvy011 SN - 2058-5888 VL - 4 IS - 2 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - von Websky, Karoline A1 - Hasan, Ahmed Abdallah Abdalrahman Mohamed A1 - Reichetzeder, Christoph A1 - Tsuprykov, Oleg A1 - Hocher, Berthold T1 - Impact of vitamin D on pregnancy-related disorders and on offspring outcome JF - The Journal of Steroid Biochemistry and Molecular Biology N2 - Observational studies from all over the world continue to find high prevalence rates of vitamin D insufficiency and deficiency in many populations, including pregnant women. Beyond its classical function as a regulator of calcium and phosphate metabolism, vitamin D elicits numerous effects in the human body. Current evidence highlights a vital role of vitamin D in mammalian gestation. During pregnancy, adaptations in maternal vitamin D metabolism lead to a physiologic increase of vitamin D levels, mainly because of an increased renal production, although other potential sources like the placenta are being discussed. A sufficient supply of mother and child with calcium and vitamin D during pregnancy ensures a healthy bone development of the fetus, whereas lack of either of these nutrients can lead to the development of rickets in the child. Moreover, vitamin D insufficiency during pregnancy has consistently been associated with adverse maternal and neonatal pregnancy outcomes. In multitudinous studies, low maternal vitamin D status was associated with a higher risk for pre-eclampsia, gestational diabetes mellitus and other gestational diseases. Likewise, several negative consequences for the fetus have been reported, including fetal growth restriction, increased risk of preterm birth and a changed susceptibility for later-life diseases. However, study results are diverging and causality has not been proven so far. Meta-analyses on the relationship between maternal vitamin D status and pregnancy outcomes revealed a wide heterogeneity of studied populations and the applied methodology in vitamin D assessment. Until today, clinical guidelines for supplementation cannot be based on high-quality evidence and it is not clear if the required intake for pregnant women differs from non-pregnant women. Long-term safety data of vitamin D supplementation in pregnant women has not been established and overdosing of vitamin D might have unfavorable effects, especially in mothers and newborns with mutations of genes involved in vitamin D metabolism. Reliable data from large observational and interventional randomized control trials are urgently needed as a basis for any detailed and safe recommendations for supplementation in the general population and, most importantly, in pregnant women. This is of utmost importance, as ensuring a sufficient vitamin D-supply of mother and child implies a great potential for the prevention of birth complications and development of diseases. KW - Vitamin D deficiency KW - Free vitamin D KW - Vitamin D binding protein KW - Epigenetics KW - DNA methylation KW - Single nucleotide polymorphism KW - Preeclampsia KW - Gestational diabetes mellitus KW - Small for gestational age KW - Long term health Y1 - 2018 U6 - https://doi.org/10.1016/j.jsbmb.2017.11.008 SN - 0960-0760 VL - 180 SP - 51 EP - 64 PB - Elsevier CY - Oxford ER - TY - THES A1 - Saussenthaler, Sophie T1 - The impact of DNA methylation on susceptibility to typ 2 diabetes in NZO mice N2 - 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. KW - epigenetics KW - DNA methylation KW - RNAseq KW - fatty liver KW - type 2 diabetes KW - HAMP Y1 - 2021 ER - TY - JOUR A1 - Saussenthaler, Sophie A1 - Ouni, Meriem A1 - Baumeier, Christian A1 - Schwerbel, Kristin A1 - Gottmann, Pascal A1 - Christmann, Sabrina A1 - Laeger, Thomas A1 - Schürmann, Annette T1 - Epigenetic regulation of hepatic Dpp4 expression in response to dietary protein JF - The journal of nutritional biochemistry N2 - Dipeptidyl peptidase 4 (DPP4) is known to be elevated in metabolic disturbances such as obesity, type 2 diabetes and fatty liver disease. Lowering DPP4 concentration by pharmacological inhibition improves glucose homeostasis and exhibits beneficial effects to reduce hepatic fat content. As factors regulating the endogenous expression of Dpp4 are unknown, the aim of this study was to examine whether the Dpp4 expression is epigenetically regulated in response to dietary components. Primary hepatocytes were treated with different macronutrients, and Dpp4 mRNA levels and DPP4 activity were evaluated. Moreover, dietary low-protein intervention was conducted in New Zealand obese (NZO) mice, and subsequently, effects on Dpp4 expression, methylation as well as plasma concentration and activity were determined. Our results indicate that Dpp4 mRNA expression is mediated by DNA methylation in several tissues. We therefore consider the Dpp4 southern shore as tissue differentially methylated region. Amino acids increased Dpp4 expression in primary hepatocytes, whereas glucose and fatty acids were without effect. Dietary protein restriction in NZO mice increased Dpp4 DNA methylation in liver leading to diminished Dpp4 expression and consequently to lowered plasma DPP4 activity. We conclude that protein restriction in the adolescent and adult states is a sufficient strategy to reduce DPP4 which in turn contributes to improve glucose homeostasis. (C) 2018 Published by Elsevier Inc. KW - DPP4 KW - DNA methylation KW - Protein restriction KW - Type 2 diabetes KW - NZO Y1 - 2019 U6 - https://doi.org/10.1016/j.jnutbio.2018.09.025 SN - 0955-2863 SN - 1873-4847 VL - 63 SP - 109 EP - 116 PB - Elsevier CY - New York ER - TY - JOUR A1 - Weyrich, Alexandra A1 - Lenz, Dorina A1 - Fickel, Jörns T1 - Environmental Change-Dependent Inherited Epigenetic Response JF - GENES N2 - Epigenetic modifications are a mechanism conveying environmental information to subsequent generations via parental germ lines. Research on epigenetic responses to environmental changes in wild mammals has been widely neglected, as well as studies that compare responses to changes in different environmental factors. Here, we focused on the transmission of DNA methylation changes to naive male offspring after paternal exposure to either diet (~40% less protein) or temperature increase (10 °C increased temperature). Because both experiments focused on the liver as the main metabolic and thermoregulation organ, we were able to decipher if epigenetic changes differed in response to different environmental changes. Reduced representation bisulfite sequencing (RRBS) revealed differentially methylated regions (DMRs) in annotated genomic regions in sons sired before (control) and after the fathers’ treatments. We detected both a highly specific epigenetic response dependent on the environmental factor that had changed that was reflected in genes involved in specific metabolic pathways, and a more general response to changes in outer stimuli reflected by epigenetic modifications in a small subset of genes shared between both responses. Our results indicated that fathers prepared their offspring for specific environmental changes by paternally inherited epigenetic modifications, suggesting a strong paternal contribution to adaptive processes. KW - DNA methylation KW - exposure KW - wild mammal species KW - inheritance KW - plasticity KW - adaptation KW - RRBS Y1 - 2018 U6 - https://doi.org/10.3390/genes10010004 SN - 2073-4425 VL - 10 IS - 1 PB - MDPI CY - Basel ER - TY - GEN A1 - Weyrich, Alexandra A1 - Jeschek, Marie A1 - Schrapers, Katharina T. A1 - Lenz, Dorina A1 - Chung, Tzu Hung A1 - Ruebensam, Kathrin A1 - Yasar, Sermin A1 - Schneemann, Markus A1 - Ortmann, Sylvia A1 - Jewgenow, Katarina A1 - Fickel, Jörns T1 - Diet changes alter paternally inherited epigenetic pattern in male Wild guinea pigs T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Epigenetic modifications, of which DNA methylation is the most stable, are a mechanism conveying environmental information to subsequent generations via parental germ lines. The paternal contribution to adaptive processes in the offspring might be crucial, but has been widely neglected in comparison to the maternal one. To address the paternal impact on the offspring's adaptability to changes in diet composition, we investigated if low protein diet (LPD) in F0 males caused epigenetic alterations in their subsequently sired sons. We therefore fed F0 male Wild guinea pigs with a diet lowered in protein content (LPD) and investigated DNA methylation in sons sired before and after their father's LPD treatment in both, liver and testis tissues. Our results point to a 'heritable epigenetic response' of the sons to the fathers' dietary change. Because we detected methylation changes also in the testis tissue, they are likely to be transmitted to the F2 generation. Gene-network analyses of differentially methylated genes in liver identified main metabolic pathways indicating a metabolic reprogramming ('metabolic shift'). Epigenetic mechanisms, allowing an immediate and inherited adaptation may thus be important for the survival of species in the context of a persistently changing environment, such as climate change. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1065 KW - DNA methylation KW - exposure KW - wild mammal species KW - inheritance KW - plasticity KW - adaptation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-460031 SN - 1866-8372 IS - 1065 ER -