Epigenetic characterization of the C3(1) SV40T mouse model of human breast cancer

Breast cancer is a heterogeneous disease, and various subtypes have been defined at the level of gene expression and epigenetic modifications, such as DNA methylation. Epigenetic alterations are attractive candidates for the development of novel biomarkers or as targets for new therapeutic approaches. Mouse models allow monitoring of tumor development from early time points of initiation to final stages of tumorigenesis, but are often poorly characterized with respect to alterations of the epigenetic landscape. Therefore, the aim of this thesis was to generated genome-wide profiles of DNA methylation and histone modifications for the C3(1)SV40TAg (C3(1)) mouse model of basal-like breast cancer and to investigate the epigenetic regulation of long noncoding RNAs. Using a genome-wide screen with Methyl CpG Immunoprecipitation followed by next generation sequencing, we identified several thousand regions with recurrent methylation alterations at different stages of C3(1) tumorigenesis. Differentially methylated genes pointed towards a luminal progenitor as tumor cell of origin in the C3(1) model, and we confirmed a link between DNA methylation and gene expression for five of these genes. Comparisons at the level of promoter methylation revealed general similarity of the C3(1) methylome to human breast cancer. Generation of a chromatin map of the C3(1) model from four histone modifications (H3K4me3, H3K4me1, H3K27ac, H3K27me3) allowed an integrative investigation of methylation changes at breast tissue-specific enhancer regions. We linked tissue-specific alterations of chromatin states in combination with DNA methylation to changes in the expression of genes with importance for mammary gland development and breast cancer. These results unveiled a potential involvement of transcription factors Etv4 (ETS variant 4) and Runx1 (runt related transcription factor 1) in C3(1) tumorigenesis that might help to understand tumor development in basal-like breast cancer. An emerging theme in epigenetic research is the capacity of long noncoding RNAs (lncRNAs) to modulate gene expression by recruitment of gene-silencing or activating complexes. Since regulation of lncRNAs expression is poorly characterized, we investigated DNA methylation changes during carcinogenesis at lncRNA promoters and their influence on neighboring proteincoding genes. Exemplarily, we demonstrated coordinated overexpression of Esrp2 (Epithelial splicing regulatory protein 2) and the lncRNA Esrp2-as (Esrp2-antisense) in C3(1) tumors that was inversely correlated with DNA methylation levels. Knockdown and overexpression of the transcripts did not provide evidence for reciprocal regulation of transcript expression. In contrast, luciferase reporter assays suggested that co-expression of both transcripts is controlled by differential methylation at a common enhancer region. These results are of clinical relevance as high levels of ESRP2 expression in human breast cancer are linked to unfavorable prognosis

Kulturen des Kopierschutzes II

Seit den 1990er Jahren war viel die Rede von Kopie und Simulation, Re­produzier­barkeit und Serialität. Doch dass schon das eigene Portemon­naie Dinge wie Geld und Personalpapiere enthält, die nicht kopiert wer­den sollen und von Normal­bürgern auch nicht kopiert werden können, wird oft vergessen. Wir leben (auch) in einer "Kultur des Kopierschutzes", in der verschiedene technische, diskursive und juristische Verfahren zu­sammenwirken, um die gesteigerte "technische Repro­duzierbarkeit", um Benjamins berühmten Ausdruck zu bemühen, im Zaum zu halten. Besonders deutlich wird das auch in den manchmal aufgeregten Diskus­sionen um den Status des Urheberrechts im Feld der digitalen Medien. Die beiden Hefte der Navigationen des Jahres 2010 sind das Ergebnis einer von Prof. Dr. Jens Schröter (Medienwissenschaft,Theorie und Praxis multi­medialer Systeme) geleiteten Projektgruppe im Masterstudiengang "Medienkul­tur". Die Studierenden haben im Rahmen des gesetzten Themas selbstständig Problemstellungen formuliert und diskutiert, dieErgebnisse dieser Arbeit sind in den beiden Heften publiziert - zusammen miteiner Reihe eingeladener Beiträge, die Aspekte abdecken, die in der Projektgruppe nicht bearbeitet werden konn­te

Modulation of Adipocyte Differentiation and Proadipogenic Gene Expression by Sulforaphane, Genistein, and Docosahexaenoic Acid as a First Step to Counteract Obesity

Obesity is characterized by excess body fat accumulation due to an increase in the size and number of differentiated mature adipocytes. Adipocyte differentiation is regulated by genetic and environmental factors, and its inhibition could represent a strategy for obesity prevention and treatment. The current study was designed with two aims: (i) to evaluate the changes in the expression of adipogenic markers (C/EBPα, PPARγ variant 1 and variant 2, and GLUT4) in 3T3-L1 murine preadipocytes at four stages of the differentiation process and (ii) to compare the effectiveness of sulforaphane, genistein, and docosahexaenoic acid in reducing lipid accumulation and modulating C/EBPα, PPARγ1, PPARγ2, and GLUT4 mRNA expression in mature adipocytes. All bioactive compounds were shown to suppress adipocyte differentiation, although with different effectiveness. These results set the stage for further studies considering natural food constituents as important agents in preventing or treating obesity

Identification of transdiagnostic psychiatric disorder subtypes using unsupervised learning

Psychiatric disorders show heterogeneous symptoms and trajectories, with current nosology not accurately reflecting their molecular etiology and the variability and symptomatic overlap within and between diagnostic classes. This heterogeneity impedes timely and targeted treatment. Our study aimed to identify psychiatric patient clusters that share clinical and genetic features and may profit from similar therapies. We used high-dimensional data clustering on deep clinical data to identify transdiagnostic groups in a discovery sample (N = 1250) of healthy controls and patients diagnosed with depression, bipolar disorder, schizophrenia, schizoaffective disorder, and other psychiatric disorders. We observed five diagnostically mixed clusters and ordered them based on severity. The least impaired cluster 0, containing most healthy controls, showed general well-being. Clusters 1-3 differed predominantly regarding levels of maltreatment, depression, daily functioning, and parental bonding. Cluster 4 contained most patients diagnosed with psychotic disorders and exhibited the highest severity in many dimensions, including medication load. Depressed patients were present in all clusters, indicating that we captured different disease stages or subtypes. We replicated all but the smallest cluster 1 in an independent sample (N = 622). Next, we analyzed genetic differences between clusters using polygenic scores (PGS) and the psychiatric family history. These genetic variables differed mainly between clusters 0 and 4 (prediction area under the receiver operating characteristic curve (AUC) = 81%;significant PGS: cross-disorder psychiatric risk, schizophrenia, and educational attainment). Our results confirm that psychiatric disorders consist of heterogeneous subtypes sharing molecular factors and symptoms. The identification of transdiagnostic clusters advances our understanding of the heterogeneity of psychiatric disorders and may support the development of personalized treatments

The Global Stratotype Sections and Points for the bases of the Selandian (Middle Paleocene) and Thanetian (Upper Paleocene) stages at Zumaia, Spain

The global stratotype sections and points for the bases of the Selandian (Middle Paleocene) and Thanetian (Upper Paleocene) stages have been defined in the coastal cliff along the Itzurun Beach at the town of Zumaia in the Basque Country, northern Spain. In the hemipelagic section exposed at Zumaia the base of the Selandian Stage has been placed at the base of the Itzurun Formation, ca. 49 m above the Cretaceous/ Paleogene boundary. At the base of the Selandian, marls replace the succession of Danian red limestone and limestone-marl couplets. The best marine, global correlation criterion for the basal Selandian is the second radiation of the important calcareous nannofossil group, the fasciculiths. Species such as Fasciculithus ulii, F. billii, F. janii, F. involutus, F.pileatus and F. tympaniformis have their first appearance in the interval from a few decimetres below up to 1.1 m above the base of the Selandian. The marker species for nannofossil Zone NP5, F. tympaniformis, first occurs 1.1 m above the base. Excellent cyclostratigraphy and magnetostratigraphy in the section creates further correlation potential, with the base of the Selandian occuring 30 precession cycles (630 kyr) above the top of magnetochron C27n. Profound changes in sedimentology related to a major sea-level fall characterize the Danian-Selandian transition in sections along the margins of the North Atlantic. The base of the Thanetian Stage is placed in the same section ca. 78 m above the Cretaceous/Paleogene boundary. It is defined at a level 2.8 m or eight precession cycles above the base of the core of the distinct clay-rich interval associated with the Mid-Paleocene Biotic Event, and it corresponds to the base of magnetochron C26n in the section. The base of the Thanetian is not associated with any significant change in marine micro-fauna or flora. The calcareous nannofossil Zone NP6, marked by the first occurrence of Heliolithus kleinpelli starts ca. 6.5 m below the base of the Thanetian. The definitions of the global stratotype points for the bases of the Selandian and Thanetian stages are in good agreements with the definitions in the historical stratotype sections in Denmark and England, respectively

Structural Correlates of Taste and Smell Loss in Encephalitis Disseminata

BACKGROUND: Olfactory dysfunction in MS patients is reported in the literature. MRI of the olfactory bulb (OB) is discussed as a promising new testing method for measuring olfactory function (OF). Aim of this study was to explore reasons for and optimize the detection of olfactory dysfunction in MS patients with MRI. MATERIALS AND METHODS: OB and olfactory brain volume was assessed within 34 MS patients by manual segmentation. Olfactory function was tested using the Threshold-Discrimination-Identification-Test (TDI), gustatory function was tested using Taste Strips (TST). RESULTS: 41% of the MS patients displayed olfactory dysfunction (8% of the control group), 16% displayed gustatory dysfunction (5% of the control group). There was a correlation between the OB volume and the number and volume of MS lesions in the olfactory brain. Olfactory brain volume correlated with the volume of lesions in the olfactory brain and the EDSS score. The TST score correlated with the number and volume of lesions in the olfactory brain. CONCLUSION: The correlation between a higher number and volume of MS lesions with a decreased OB and olfactory brain volume could help to explain olfactory dysfunction

Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

Amyloid-beta 42 (A beta 42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for A beta 42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple A beta 42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.Peer reviewe

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Shared genetic risk between eating disorder- and substance-use-related phenotypes:Evidence from genome-wide association studies

First published: 16 February 202