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5 Publications matching the given criteria: (Clear all filters)
Published year: 20175
IRS1 DNA promoter methylation and expression in human adipose tissue are related to fat distribution and metabolic traits.
LHA - Leipzig Health Atlas

Abstract (Expand)

The SNP variant rs2943650 near IRS1 gene locus was previously associated with decreased body fat and IRS1 gene expression as well as an adverse metabolic profile in humans. Here, we hypothesize that … these effects may be mediated by an interplay with epigenetic alterations. We measured IRS1 promoter DNA methylation and mRNA expression in paired human subcutaneous and omental visceral adipose tissue samples (SAT and OVAT) from 146 and 41 individuals, respectively. Genotyping of rs2943650 was performed in all individuals (N = 146). We observed a significantly higher IRS1 promoter DNA methylation in OVAT compared to SAT (N = 146, P = 8.0 x 10(-6)), while expression levels show the opposite effect direction (N = 41, P = 0.011). OVAT and SAT methylation correlated negatively with IRS1 gene expression in obese subjects (N = 16, P = 0.007 and P = 0.010). The major T-allele is related to increased DNA methylation in OVAT (N = 146, P = 0.019). Finally, DNA methylation and gene expression in OVAT correlated with anthropometric traits (waist- circumference waist-to-hip ratio) and parameters of glucose metabolism in obese individuals. Our data suggest that the association between rs2943650 near the IRS1 gene locus with clinically relevant variables may at least be modulated by changes in DNA methylation that translates into altered IRS1 gene expression.

Authors: K. Rohde, M. Klos, L. Hopp, X. Liu, M. Keller, M. Stumvoll, A. Dietrich, M. R. Schon, D. Gartner, T. Lohmann, M. Dressler, P. Kovacs, H. Binder, M. Bluher, Y. Bottcher

Date Published: 28th Sep 2017

Publication Type: Not specified

Genomic and transcriptomic heterogeneity of colorectal tumours arising in Lynch syndrome.
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

Colorectal cancer (CRC) arising in Lynch syndrome (LS) comprises tumours with constitutional mutations in DNA mismatch repair genes. There is still a lack of whole-genome and transcriptome studies of … LS-CRC to address questions about similarities and differences in mutation and gene expression characteristics between LS-CRC and sporadic CRC, about the molecular heterogeneity of LS-CRC, and about specific mechanisms of LS-CRC genesis linked to dysfunctional mismatch repair in LS colonic mucosa and the possible role of immune editing. Here, we provide a first molecular characterization of LS tumours and of matched tumour-distant reference colonic mucosa based on whole-genome DNA-sequencing and RNA-sequencing analyses. Our data support two subgroups of LS-CRCs, G1 and G2, whereby G1 tumours show a higher number of somatic mutations, a higher amount of microsatellite slippage, and a different mutation spectrum. The gene expression phenotypes support this difference. Reference mucosa of G1 shows a strong immune response associated with the expression of HLA and immune checkpoint genes and the invasion of CD4+ T cells. Such an immune response is not observed in LS tumours, G2 reference and normal (non-Lynch) mucosa, and sporadic CRC. We hypothesize that G1 tumours are edited for escape from a highly immunogenic microenvironment via loss of HLA presentation and T-cell exhaustion. In contrast, G2 tumours seem to develop in a less immunogenic microenvironment where tumour-promoting inflammation parallels tumourigenesis. Larger studies on non-neoplastic mucosa tissue of mutation carriers are required to better understand the early phases of emerging tumours. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Authors: H. Binder, L. Hopp, M. R. Schweiger, S. Hoffmann, F. Juhling, M. Kerick, B. Timmermann, S. Siebert, C. Grimm, L. Nersisyan, A. Arakelyan, M. Herberg, P. Buske, H. Loeffler-Wirth, M. Rosolowski, C. Engel, J. Przybilla, M. Peifer, N. Friedrichs, G. Moeslein, M. Odenthal, M. Hussong, S. Peters, S. Holzapfel, J. Nattermann, R. Hueneburg, W. Schmiegel, B. Royer-Pokora, S. Aretz, M. Kloth, M. Kloor, R. Buettner, J. Galle, M. Loeffler

Date Published: 21st Jul 2017

Publication Type: Not specified

Human Diseases: Lynch syndrome, colorectal cancer

Genome-wide DNA promoter methylation and transcriptome analysis in human adipose tissue unravels novel candidate genes for obesity.
LHA - Leipzig Health Atlas

Abstract (Expand)

OBJECTIVE/METHODS: DNA methylation plays an important role in obesity and related metabolic complications. We examined genome-wide DNA promoter methylation along with mRNA profiles in paired samples … of human subcutaneous adipose tissue (SAT) and omental visceral adipose tissue (OVAT) from non-obese vs. obese individuals. RESULTS: We identified negatively correlated methylation and expression of several obesity-associated genes in our discovery dataset and in silico replicated ETV6 in two independent cohorts. Further, we identified six adipose tissue depot-specific genes (HAND2, HOXC6, PPARG, SORBS2, CD36, and CLDN1). The effects were further supported in additional independent cohorts. Our top hits might play a role in adipogenesis and differentiation, obesity, lipid metabolism, and adipose tissue expandability. Finally, we show that in vitro methylation of SORBS2 directly represses gene expression. CONCLUSIONS: Taken together, our data show distinct tissue specific epigenetic alterations which associate with obesity.

Authors: M. Keller, L. Hopp, X. Liu, T. Wohland, K. Rohde, R. Cancello, M. Klos, K. Bacos, M. Kern, F. Eichelmann, A. Dietrich, M. R. Schon, D. Gartner, T. Lohmann, M. Dressler, M. Stumvoll, P. Kovacs, A. M. DiBlasio, C. Ling, H. Binder, M. Bluher, Y. Bottcher

Date Published: 27th Jan 2017

Publication Type: Not specified

Human Diseases: obesity

Mapping heterogeneity in patient-derived melanoma cultures by single-cell RNA-seq.
Leipzig Melanoma Studies

Abstract (Expand)

Recent technological advances in single-cell genomics make it possible to analyze cellular heterogeneity of tumor samples. Here, we applied single-cell RNA-seq to measure the transcriptomes of 307 … single cells cultured from three biopsies of three different patients with a BRAF/NRAS wild type, BRAF mutant/NRAS wild type and BRAF wild type/NRAS mutant melanoma metastasis, respectively. Analysis based on self-organizing maps identified sub-populations defined by multiple gene expression modules involved in proliferation, oxidative phosphorylation, pigmentation and cellular stroma. Gene expression modules had prognostic relevance when compared with gene expression data from published melanoma samples and patient survival data. We surveyed kinome expression patterns across sub-populations of the BRAF/NRAS wild type sample and found that CDK4 and CDK2 were consistently highly expressed in the majority of cells, suggesting that these kinases might be involved in melanoma progression. Treatment of cells with the CDK4 inhibitor palbociclib restricted cell proliferation to a similar, and in some cases greater, extent than MAPK inhibitors. Finally, we identified a low abundant sub-population in this sample that highly expressed a module containing ABC transporter ABCB5, surface markers CD271 and CD133, and multiple aldehyde dehydrogenases (ALDHs). Patient-derived cultures of the BRAF mutant/NRAS wild type and BRAF wild type/NRAS mutant metastases showed more homogeneous single-cell gene expression patterns with gene expression modules for proliferation and ABC transporters. Taken together, our results describe an intertumor and intratumor heterogeneity in melanoma short-term cultures which might be relevant for patient survival, and suggest promising targets for new treatment approaches in melanoma therapy.

Authors: T. Gerber, E. Willscher, H. Loeffler-Wirth, L. Hopp, D. Schadendorf, M. Schartl, U. Anderegg, G. Camp, B. Treutlein, H. Binder, M. Kunz

Date Published: 3rd Jan 2017

Publication Type: Not specified

Human Diseases: melanoma

Personalized disease phenotypes from massive omics data.
LHA - Leipzig Health Atlas

Abstract (Expand)

Application of new high-throughput technologies in molecular medicine collects massive data for hundreds to thousands of persons in large cohort studies by characterizing the phenotype of each individual … on a personalized basis. The chapter aims at increasing our understanding of disease genesis and progression and to improve diagnosis and treatment. New methods are needed to handle such "big data." Machine learning enables one to recognize and to visualize complex data patterns and to make decisions potentially relevant for diagnosis and treatment. The authors address these tasks by applying the method of self-organizing maps and present worked examples from different disease entities of the colon ranging from inflammation to cancer.

Authors: Hans Binder, Lydia Hopp, K. Lembcke, Henry Löffler-Wirth

Date Published: 2017

Publication Type: Not specified

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