Publications by authors named "Andreas J Gruber"

21 Publications

  • Page 1 of 1

Germline MBD4 deficiency causes a multi-tumor predisposition syndrome.

Am J Hum Genet 2022 May 22;109(5):953-960. Epub 2022 Apr 22.

Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Parkville, VIC, Australia; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, Australia.

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2022.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9118112PMC
May 2022

Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes.

Nat Commun 2021 11 26;12(1):6946. Epub 2021 Nov 26.

Center for Clinical Cancer Genetics and Global Health, Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA.

Black women across the African diaspora experience more aggressive breast cancer with higher mortality rates than white women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast cancers, with RNA-seq in a subset, from women in Nigeria in comparison with The Cancer Genome Atlas (n = 76) reveal a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations with a 10.5-year younger age at diagnosis. We also find non-coding mutations in bona fide drivers (ZNF217 and SYPL1) and a previously unreported INDEL signature strongly associated with African ancestry proportion, underscoring the need to expand inclusion of diverse populations in biomedical research. Finally, we demonstrate that characterizing tumors for homologous recombination deficiency has significant clinical relevance in stratifying patients for potentially life-saving therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-27079-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626467PMC
November 2021

Genome-wide bioinformatic analyses predict key host and viral factors in SARS-CoV-2 pathogenesis.

Commun Biol 2021 05 17;4(1):590. Epub 2021 May 17.

Department of Computer Science, University of Miami, Coral Gables, FL, USA.

The novel betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a worldwide pandemic (COVID-19) after emerging in Wuhan, China. Here we analyzed public host and viral RNA sequencing data to better understand how SARS-CoV-2 interacts with human respiratory cells. We identified genes, isoforms and transposable element families that are specifically altered in SARS-CoV-2-infected respiratory cells. Well-known immunoregulatory genes including CSF2, IL32, IL-6 and SERPINA3 were differentially expressed, while immunoregulatory transposable element families were upregulated. We predicted conserved interactions between the SARS-CoV-2 genome and human RNA-binding proteins such as the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) and eukaryotic initiation factor 4 (eIF4b). We also identified a viral sequence variant with a statistically significant skew associated with age of infection, that may contribute to intracellular host-pathogen interactions. These findings can help identify host mechanisms that can be targeted by prophylactics and/or therapeutics to reduce the severity of COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42003-021-02095-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128904PMC
May 2021

Reply to 'A different perspective on alternative cleavage and polyadenylation'.

Nat Rev Genet 2020 01;21(1):63-64

Computational and Systems Biology, Biozentrum, University of Basel, Basel, Switzerland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41576-019-0199-yDOI Listing
January 2020

PolyASite 2.0: a consolidated atlas of polyadenylation sites from 3' end sequencing.

Nucleic Acids Res 2020 01;48(D1):D174-D179

Biozentrum, University of Basel, Basel, Switzerland.

Generated by 3' end cleavage and polyadenylation at alternative polyadenylation (poly(A)) sites, alternative terminal exons account for much of the variation between human transcript isoforms. More than a dozen protocols have been developed so far for capturing and sequencing RNA 3' ends from a variety of cell types and species. In previous studies, we have used these data to uncover novel regulatory signals and cell type-specific isoforms. Here we present an update of the PolyASite (https://polyasite.unibas.ch) resource of poly(A) sites, constructed from publicly available human, mouse and worm 3' end sequencing datasets by enforcing uniform quality measures, including the flagging of putative internal priming sites. Through integrated processing of all data, we identified and clustered sites that are closely spaced and share polyadenylation signals, as these are likely the result of stochastic variations in processing. For each cluster, we identified the representative - most frequently processed - site and estimated the relative use in the transcriptome across all samples. We have established a modern web portal for efficient finding, exploration and export of data. Database generation is fully automated, greatly facilitating incorporation of new datasets and the updating of underlying genome resources.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gkz918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145510PMC
January 2020

Alternative cleavage and polyadenylation in health and disease.

Nat Rev Genet 2019 10 2;20(10):599-614. Epub 2019 Jul 2.

Computational and Systems Biology, Biozentrum, University of Basel, Basel, Switzerland.

Most human genes have multiple sites at which RNA 3' end cleavage and polyadenylation can occur, enabling the expression of distinct transcript isoforms under different conditions. Novel methods to sequence RNA 3' ends have generated comprehensive catalogues of polyadenylation (poly(A)) sites; their analysis using innovative computational methods has revealed how poly(A) site choice is regulated by core RNA 3' end processing factors, such as cleavage factor I and cleavage and polyadenylation specificity factor, as well as by other RNA-binding proteins, particularly splicing factors. Here, we review the experimental and computational methods that have enabled the global mapping of mRNA and of long non-coding RNA 3' ends, quantification of the resulting isoforms and the discovery of regulators of alternative cleavage and polyadenylation (APA). We highlight the different types of APA-derived isoforms and their functional differences, and illustrate how APA contributes to human diseases, including cancer and haematological, immunological and neurological diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41576-019-0145-zDOI Listing
October 2019

Terminal exon characterization with TECtool reveals an abundance of cell-specific isoforms.

Nat Methods 2018 10 10;15(10):832-836. Epub 2018 Sep 10.

Computational and Systems Biology, Biozentrum, University of Basel, Basel, Switzerland.

Sequencing of RNA 3' ends has uncovered numerous sites that do not correspond to the termination sites of known transcripts. Through their 3' untranslated regions, protein-coding RNAs interact with RNA-binding proteins and microRNAs, which regulate many properties, including RNA stability and subcellular localization. We developed the terminal exon characterization (TEC) tool ( http://tectool.unibas.ch ), which can be used with RNA-sequencing data from any species for which a genome annotation that includes sites of RNA cleavage and polyadenylation is available. We discovered hundreds of previously unknown isoforms and cell-type-specific terminal exons in human cells. Ribosome profiling data revealed that many of these isoforms were translated. By applying TECtool to single-cell sequencing data, we found that the newly identified isoforms were expressed in subpopulations of cells. Thus, TECtool enables the identification of previously unknown isoforms in well-studied cell systems and in rare cell types.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41592-018-0114-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611301PMC
October 2018

Single-cell mRNA profiling reveals the hierarchical response of miRNA targets to miRNA induction.

Mol Syst Biol 2018 08 27;14(8):e8266. Epub 2018 Aug 27.

Biozentrum, University of Basel and Swiss Institute of Bioinformatics, Basel, Switzerland

miRNAs are small RNAs that regulate gene expression post-transcriptionally. By repressing the translation and promoting the degradation of target mRNAs, miRNAs may reduce the cell-to-cell variability in protein expression, induce correlations between target expression levels, and provide a layer through which targets can influence each other's expression as "competing RNAs" (ceRNAs). However, experimental evidence for these behaviors is limited. Combining mathematical modeling with RNA sequencing of individual human embryonic kidney cells in which the expression of two distinct miRNAs was induced over a wide range, we have inferred parameters describing the response of hundreds of miRNA targets to miRNA induction. Individual targets have widely different response dynamics, and only a small proportion of predicted targets exhibit high sensitivity to miRNA induction. Our data reveal for the first time the response parameters of the entire network of endogenous miRNA targets to miRNA induction, demonstrating that miRNAs correlate target expression and at the same time increase the variability in expression of individual targets across cells. The approach is generalizable to other miRNAs and post-transcriptional regulators to improve the understanding of gene expression dynamics in individual cell types.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110312PMC
http://dx.doi.org/10.15252/msb.20188266DOI Listing
August 2018

Discovery of physiological and cancer-related regulators of 3' UTR processing with KAPAC.

Genome Biol 2018 03 28;19(1):44. Epub 2018 Mar 28.

Computational and Systems Biology, Biozentrum, University of Basel, Klingelbergstrasse 50-70, 4056, Basel, Switzerland.

3' Untranslated regions (3' UTRs) length is regulated in relation to cellular state. To uncover key regulators of poly(A) site use in specific conditions, we have developed PAQR, a method for quantifying poly(A) site use from RNA sequencing data and KAPAC, an approach that infers activities of oligomeric sequence motifs on poly(A) site choice. Application of PAQR and KAPAC to RNA sequencing data from normal and tumor tissue samples uncovers motifs that can explain changes in cleavage and polyadenylation in specific cancers. In particular, our analysis points to polypyrimidine tract binding protein 1 as a regulator of poly(A) site choice in glioblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13059-018-1415-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5875010PMC
March 2018

3' End Sequencing Library Preparation with A-seq2.

J Vis Exp 2017 10 10(128). Epub 2017 Oct 10.

Computational and Systems Biology, Biozentrum, University of Basel; Swiss Institute of Bioinformatics, Biozentrum, University of Basel;

Studies in the last decade have revealed a complex and dynamic variety of pre-mRNA cleavage and polyadenylation reactions. mRNAs with long 3' untranslated regions (UTRs) are generated in differentiated cells whereas proliferating cells preferentially express transcripts with short 3'UTRs. We describe the A-seq protocol, now at its second version, which was developed to map polyadenylation sites genome-wide and study the regulation of pre-mRNA 3' end processing. Also this current protocol takes advantage of the polyadenylate (poly(A)) tails that are added during the biogenesis of most mammalian mRNAs to enrich for fully processed mRNAs. A DNA adaptor with deoxyuracil at its fourth position allows the precise processing of mRNA 3' end fragments for sequencing. Not including the cell culture and the overnight ligations, the protocol requires about 8 h hands-on time. Along with it, an easy-to-use software package for the analysis of the derived sequencing data is provided. A-seq2 and the associated analysis software provide an efficient and reliable solution to the mapping of pre-mRNA 3' ends in a wide range of conditions, from 10 or fewer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3791/56129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752398PMC
October 2017

TFAP2A is a component of the ZEB1/2 network that regulates TGFB1-induced epithelial to mesenchymal transition.

Biol Direct 2017 04 17;12(1). Epub 2017 Apr 17.

Biozentrum, University of Basel, Klingelbergstrasse 50-70, CH-4056, Basel, Switzerland.

Background: The transition between epithelial and mesenchymal phenotypes (EMT) occurs in a variety of contexts. It is critical for mammalian development and it is also involved in tumor initiation and progression. Master transcription factor (TF) regulators of this process are conserved between mouse and human.

Methods: From a computational analysis of a variety of high-throughput sequencing data sets we initially inferred that TFAP2A is connected to the core EMT network in both species. We then analysed publicly available human breast cancer data for TFAP2A expression and also studied the expression (by mRNA sequencing), activity (by monitoring the expression of its predicted targets), and binding (by electrophoretic mobility shift assay and chromatin immunoprecipitation) of this factor in a mouse mammary gland EMT model system (NMuMG) cell line.

Results: We found that upon induction of EMT, the activity of TFAP2A, reflected in the expression level of its predicted targets, is up-regulated in a variety of systems, both murine and human, while TFAP2A's expression is increased in more "stem-like" cancers. We provide strong evidence for the direct interaction between the TFAP2A TF and the ZEB2 promoter and we demonstrate that this interaction affects ZEB2 expression. Overexpression of TFAP2A from an exogenous construct perturbs EMT, however, in a manner similar to the downregulation of endogenous TFAP2A that takes place during EMT.

Conclusions: Our study reveals that TFAP2A is a conserved component of the core network that regulates EMT, acting as a repressor of many genes, including ZEB2.

Reviewers: This article has been reviewed by Dr. Martijn Huynen and Dr. Nicola Aceto.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13062-017-0180-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392957PMC
April 2017

Differential transcriptional responses to Ebola and Marburg virus infection in bat and human cells.

Sci Rep 2016 10 7;6:34589. Epub 2016 Oct 7.

Theoretical Biochemistry Group, Institute of Theoretical Chemistry, University of Vienna, Währingerstraße 17, 1090, Vienna, Austria.

The unprecedented outbreak of Ebola in West Africa resulted in over 28,000 cases and 11,000 deaths, underlining the need for a better understanding of the biology of this highly pathogenic virus to develop specific counter strategies. Two filoviruses, the Ebola and Marburg viruses, result in a severe and often fatal infection in humans. However, bats are natural hosts and survive filovirus infections without obvious symptoms. The molecular basis of this striking difference in the response to filovirus infections is not well understood. We report a systematic overview of differentially expressed genes, activity motifs and pathways in human and bat cells infected with the Ebola and Marburg viruses, and we demonstrate that the replication of filoviruses is more rapid in human cells than in bat cells. We also found that the most strongly regulated genes upon filovirus infection are chemokine ligands and transcription factors. We observed a strong induction of the JAK/STAT pathway, of several genes encoding inhibitors of MAP kinases (DUSP genes) and of PPP1R15A, which is involved in ER stress-induced cell death. We used comparative transcriptomics to provide a data resource that can be used to identify cellular responses that might allow bats to survive filovirus infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep34589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054393PMC
October 2016

A comprehensive analysis of 3' end sequencing data sets reveals novel polyadenylation signals and the repressive role of heterogeneous ribonucleoprotein C on cleavage and polyadenylation.

Genome Res 2016 08 5;26(8):1145-59. Epub 2016 Jul 5.

Computational and Systems Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.

Alternative polyadenylation (APA) is a general mechanism of transcript diversification in mammals, which has been recently linked to proliferative states and cancer. Different 3' untranslated region (3' UTR) isoforms interact with different RNA-binding proteins (RBPs), which modify the stability, translation, and subcellular localization of the corresponding transcripts. Although the heterogeneity of pre-mRNA 3' end processing has been established with high-throughput approaches, the mechanisms that underlie systematic changes in 3' UTR lengths remain to be characterized. Through a uniform analysis of a large number of 3' end sequencing data sets, we have uncovered 18 signals, six of which are novel, whose positioning with respect to pre-mRNA cleavage sites indicates a role in pre-mRNA 3' end processing in both mouse and human. With 3' end sequencing we have demonstrated that the heterogeneous ribonucleoprotein C (HNRNPC), which binds the poly(U) motif whose frequency also peaks in the vicinity of polyadenylation (poly(A)) sites, has a genome-wide effect on poly(A) site usage. HNRNPC-regulated 3' UTRs are enriched in ELAV-like RBP 1 (ELAVL1) binding sites and include those of the CD47 gene, which participate in the recently discovered mechanism of 3' UTR-dependent protein localization (UDPL). Our study thus establishes an up-to-date, high-confidence catalog of 3' end processing sites and poly(A) signals, and it uncovers an important role of HNRNPC in regulating 3' end processing. It further suggests that U-rich elements mediate interactions with multiple RBPs that regulate different stages in a transcript's life cycle.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/gr.202432.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971764PMC
August 2016

Comparative assessment of methods for the computational inference of transcript isoform abundance from RNA-seq data.

Genome Biol 2015 Jul 23;16:150. Epub 2015 Jul 23.

Biozentrum, University of Basel and Swiss Institute of Bioinformatics, Basel, Switzerland.

Background: Understanding the regulation of gene expression, including transcription start site usage, alternative splicing, and polyadenylation, requires accurate quantification of expression levels down to the level of individual transcript isoforms. To comparatively evaluate the accuracy of the many methods that have been proposed for estimating transcript isoform abundance from RNA sequencing data, we have used both synthetic data as well as an independent experimental method for quantifying the abundance of transcript ends at the genome-wide level.

Results: We found that many tools have good accuracy and yield better estimates of gene-level expression compared to commonly used count-based approaches, but they vary widely in memory and runtime requirements. Nucleotide composition and intron/exon structure have comparatively little influence on the accuracy of expression estimates, which correlates most strongly with transcript/gene expression levels. To facilitate the reproduction and further extension of our study, we provide datasets, source code, and an online analysis tool on a companion website, where developers can upload expression estimates obtained with their own tool to compare them to those inferred by the methods assessed here.

Conclusions: As many methods for quantifying isoform abundance with comparable accuracy are available, a user's choice will likely be determined by factors such as the memory and runtime requirements, as well as the availability of methods for downstream analyses. Sequencing-based methods to quantify the abundance of specific transcript regions could complement validation schemes based on synthetic data and quantitative PCR in future or ongoing assessments of RNA-seq analysis methods.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13059-015-0702-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511015PMC
July 2015

Exploiting the multiplexing capabilities of tandem mass tags for high-throughput estimation of cellular protein abundances by mass spectrometry.

Methods 2015 Sep 4;85:100-107. Epub 2015 May 4.

Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland. Electronic address:

The generation of dynamic models of biological processes critically depends on the determination of precise cellular concentrations of biomolecules. Measurements of system-wide absolute protein levels are particularly valuable information in systems biology. Recently, mass spectrometry based proteomics approaches have been developed to estimate protein concentrations on a proteome-wide scale. However, for very complex proteomes, fractionation steps are required, increasing samples number and instrument analysis time. As a result, the number of full proteomes that can be routinely analyzed is limited. Here we combined absolute quantification strategies with the multiplexing capabilities of isobaric tandem mass tags to determine cellular protein abundances in a high throughput and proteome-wide scale even for highly complex biological systems, such as a whole human cell line. We generated two independent data sets to demonstrate the power of the approach regarding sample throughput, dynamic range, quantitative precision and accuracy as well as proteome coverage in comparison to existing mass spectrometry based strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymeth.2015.04.032DOI Listing
September 2015

Global 3' UTR shortening has a limited effect on protein abundance in proliferating T cells.

Nat Commun 2014 Nov 21;5:5465. Epub 2014 Nov 21.

Computational and Systems Biology, Biozentrum, University of Basel and Swiss Institute of Bioinformatics, Basel CH-4056, Switzerland.

Alternative polyadenylation is a cellular mechanism that generates mRNA isoforms differing in their 3' untranslated regions (3' UTRs). Changes in polyadenylation site usage have been described upon induction of proliferation in resting cells, but the underlying mechanism and functional significance of this phenomenon remain largely unknown. To understand the functional consequences of shortened 3' UTR isoforms in a physiological setting, we used 3' end sequencing and quantitative mass spectrometry to determine polyadenylation site usage, mRNA and protein levels in murine and human naive and activated T cells. Although 3' UTR shortening in proliferating cells is conserved between human and mouse, orthologous genes do not exhibit similar expression of alternative 3' UTR isoforms. We generally find that 3' UTR shortening is not accompanied by a corresponding change in mRNA and protein levels. This suggests that although 3' UTR shortening may lead to changes in the RNA-binding protein interactome, it has limited effects on protein output.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms6465DOI Listing
November 2014

Embryonic stem cell-specific microRNAs contribute to pluripotency by inhibiting regulators of multiple differentiation pathways.

Nucleic Acids Res 2014 Aug 16;42(14):9313-26. Epub 2014 Jul 16.

Biozentrum, University of Basel, Klingelberstrasse 50-70, CH-4056 Basel, Switzerland

The findings that microRNAs (miRNAs) are essential for early development in many species and that embryonic miRNAs can reprogram somatic cells into induced pluripotent stem cells suggest that these miRNAs act directly on transcriptional and chromatin regulators of pluripotency. To elucidate the transcription regulatory networks immediately downstream of embryonic miRNAs, we extended the motif activity response analysis approach that infers the regulatory impact of both transcription factors (TFs) and miRNAs from genome-wide expression states. Applying this approach to multiple experimental data sets generated from mouse embryonic stem cells (ESCs) that did or did not express miRNAs of the ESC-specific miR-290-295 cluster, we identified multiple TFs that are direct miRNA targets, some of which are known to be active during cell differentiation. Our results provide new insights into the transcription regulatory network downstream of ESC-specific miRNAs, indicating that these miRNAs act on cell cycle and chromatin regulators at several levels and downregulate TFs that are involved in the innate immune response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gku544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132708PMC
August 2014

Pegylated IFN-α regulates hepatic gene expression through transient Jak/STAT activation.

J Clin Invest 2014 Apr 24;124(4):1568-81. Epub 2014 Feb 24.

The use of pegylated interferon-α (pegIFN-α) has replaced unmodified recombinant IFN-α for the treatment of chronic viral hepatitis. While the superior antiviral efficacy of pegIFN-α is generally attributed to improved pharmacokinetic properties, the pharmacodynamic effects of pegIFN-α in the liver have not been studied. Here, we analyzed pegIFN-α-induced signaling and gene regulation in paired liver biopsies obtained prior to treatment and during the first week following pegIFN-α injection in 18 patients with chronic hepatitis C. Despite sustained high concentrations of pegIFN-α in serum, the Jak/STAT pathway was activated in hepatocytes only on the first day after pegIFN-α administration. Evaluation of liver biopsies revealed that pegIFN-α induces hundreds of genes that can be classified into four clusters based on different temporal expression profiles. In all clusters, gene transcription was mainly driven by IFN-stimulated gene factor 3 (ISGF3). Compared with conventional IFN-α therapy, pegIFN-α induced a broader spectrum of gene expression, including many genes involved in cellular immunity. IFN-induced secondary transcription factors did not result in additional waves of gene expression. Our data indicate that the superior antiviral efficacy of pegIFN-α is not the result of prolonged Jak/STAT pathway activation in hepatocytes, but rather is due to induction of additional genes that are involved in cellular immune responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI70408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3973080PMC
April 2014

ISMARA: automated modeling of genomic signals as a democracy of regulatory motifs.

Genome Res 2014 May 10;24(5):869-84. Epub 2014 Feb 10.

Biozentrum, University of Basel, and Swiss Institute of Bioinformatics, CH-4056 Basel, Switzerland.

Accurate reconstruction of the regulatory networks that control gene expression is one of the key current challenges in molecular biology. Although gene expression and chromatin state dynamics are ultimately encoded by constellations of binding sites recognized by regulators such as transcriptions factors (TFs) and microRNAs (miRNAs), our understanding of this regulatory code and its context-dependent read-out remains very limited. Given that there are thousands of potential regulators in mammals, it is not practical to use direct experimentation to identify which of these play a key role for a particular system of interest. We developed a methodology that models gene expression or chromatin modifications in terms of genome-wide predictions of regulatory sites and completely automated it into a web-based tool called ISMARA (Integrated System for Motif Activity Response Analysis). Given only gene expression or chromatin state data across a set of samples as input, ISMARA identifies the key TFs and miRNAs driving expression/chromatin changes and makes detailed predictions regarding their regulatory roles. These include predicted activities of the regulators across the samples, their genome-wide targets, enriched gene categories among the targets, and direct interactions between the regulators. Applying ISMARA to data sets from well-studied systems, we show that it consistently identifies known key regulators ab initio. We also present a number of novel predictions including regulatory interactions in innate immunity, a master regulator of mucociliary differentiation, TFs consistently disregulated in cancer, and TFs that mediate specific chromatin modifications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/gr.169508.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009616PMC
May 2014

Modulation of epigenetic regulators and cell fate decisions by miRNAs.

Epigenomics 2013 Dec;5(6):671-83

Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056, Basel, Switzerland.

Mammalian gene expression is controlled at multiple levels by a variety of regulators, including chromatin modifiers, transcription factors and miRNAs. The latter are small, ncRNAs that inhibit the expression of target mRNAs by reducing both their stability and translation rate. In this review, we summarize the recent work towards characterizing miRNA targets that are themselves involved in the regulation of gene expression at the epigenetic level. Epigenetic regulators are strongly enriched among the predicted targets of miRNAs, which may contribute to the documented importance of miRNAs for pluripotency, organism development and somatic cell reprogramming.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/epi.13.65DOI Listing
December 2013
-->