Biology subjects

Kepper, N.

Publications and source records attributed to Kepper, N..

3 recordsLinked to original sources

bioRxiv2022

Epigenetic signals that direct cell type specific interferon beta response in mouse cells

The antiviral response induced by type I interferon (IFN) via the JAK-STAT signaling cascade activates hundreds of IFN-stimulated genes (ISGs). While this response occurs essentially in all human and mouse tissues it varies between different cell types. However, the linkage between the underlying epigenetic features and the ISG pattern of a given cell is not well understood. We mapped ISGs, binding sites of the STAT1 and STAT2 transcription factors and chromatin features in three different mouse cell types (embryonic stem cells, neural progenitor cells and embryonic fibroblasts) before and after treatment with IFN{beta}. The analysis included gene expression, chromatin accessibility and histone H3 lysine modification by acetylation (ac) and mono-/tri-methylation (me1, me3). A large fraction of ISGs and STAT binding sites were cell type specific with promoter binding of a STAT1-STAT2 complex (STAT1/2) being a key driver of ISG induction. Furthermore, STAT1/2 binding to putative enhancers at intergenic and intronic sites induced ISG expression as inferred from a chromatin co-accessibility analysis. STAT1/2 binding was dependent on the chromatin context and positively correlated with pre-existing H3K4me1 and H3K27ac marks in an open chromatin state while the presence of H3K27me3 had an inhibitory effect. Thus, chromatin features present before stimulation represent an additional regulatory layer for the cell type specific antiviral response.

molecular biology↗

bioRxiv2017

TelNet - a database for human and yeast genes involved in telomere maintenance

The ends of linear chromosomes, the telomeres, comprise repetitive DNA sequences that are protected by the shelterin protein complex. Cancer cells need to extend these telomere repeats for their unlimited proliferation, either by reactivating the reverse transcriptase telomerase or by using the alternative lengthening of telomeres (ALT) pathway. The different telomere maintenance (TM) mechanisms appear to involve hundreds of proteins but their telomere repeat length related activities are only partly understood. Currently, a database that integrates information on TM relevant genes is missing. To provide a reference for studies that dissect TM features, we here introduce the TelNet database at http://www.cancertelsys.org/telnet/. It offers a comprehensive compilation of more than 2,000 human and over 1,100 yeast genes linked to telomere maintenance. These genes were annotated in terms of TM mechanism, associated specific functions and orthologous genes, a TM significance score and information from peer-reviewed literature. This TM information can be retrieved via different search and view modes and evaluated for a set of genes on a statistics page. With these features TelNet can be integrated into the annotation of genes identified from bioinformatics analysis pipelines to determine possible connections with TM networks as illustrated by an exemplary application. We anticipate that TelNet will be a helpful resource for researchers that study TM processes.

cancer biology↗

bioRxiv2017

Dissecting telomere maintenance mechanisms in pediatric glioblastoma

Pediatric glioblastoma (pedGBM) represent a highly malignant primary brain tumor with recurrent mutations in the chromatin remodeler ATRX and the histone variant H3.3 that is typically associated with a fatal outcome. ATRX acts as suppressor of the alternative lengthening of telomeres (ALT) pathway, which is frequently activated in pedGBM. However, telomere features of pedGBMs have not been studied in detail, and ALT-positive model cell lines are lacking. Here, we systematically characterized a panel of pedGBM models that carry a representative set of recurrent genomic mutations for a variety of telomere features. These included the presence of ALT-associated promyelocytic leukemia nuclear bodies and C-circles, a specific type of extrachromosomal telomeric repeats, the telomere repeat content, and phosphorylation of histone H3.3 at serine 31. From an integrated analysis of seven pedGBM cell lines and 57 primary tumor samples we identified cell lines and tumors that represent the different telomere maintenance mechanisms and conclude the following: (i) A positive signal in the C-circle assay is a reliable ALT marker. (ii) ALT features occur heterogeneously and one pedGBM subgroup uses a non-canonical ALT mechanism in the presence of wild-type ATRX. (iii) The spreading of H3.3S31 phosphorylation during mitosis is associated with loss of ATRX but not with ALT per se. (iv) In contrast to a previous study in glioma stem cells, we did not find a hypersensitivity of ALT cells towards the ATR inhibitor VE-821. (v) ALT-positive pedGBMs can be reliably identified from a classification scheme developed here that evaluates various combinations of cytogenetic and/or genomic data. Thus, our findings elucidate further details of the ALT pathway in pedGBMs, provide valuable models for evaluating ALT targeted therapies in a preclinical setting, and introduce an ALT classification scheme for primary tumor samples.

cancer biology↗