123 results found
Cantone I, Dharmalingam G, Chan YW, et al., 2017, Allele-specific analysis of cell fusion-mediated pluripotent reprograming reveals distinct and predictive susceptibilities of human X-linked genes to reactivation., Genome Biol, Vol: 18
BACKGROUND: Inactivation of one X chromosome is established early in female mammalian development and can be reversed in vivo and in vitro when pluripotency factors are re-expressed. The extent of reactivation along the inactive X chromosome (Xi) and the determinants of locus susceptibility are, however, poorly understood. Here we use cell fusion-mediated pluripotent reprograming to study human Xi reactivation and allele-specific single nucleotide polymorphisms (SNPs) to identify reactivated loci. RESULTS: We show that a subset of human Xi genes is rapidly reactivated upon re-expression of the pluripotency network. These genes lie within the most evolutionary recent segments of the human X chromosome that are depleted of LINE1 and enriched for SINE elements, predicted to impair XIST spreading. Interestingly, this cadre of genes displays stochastic Xi expression in human fibroblasts ahead of reprograming. This stochastic variability is evident between clones, by RNA-sequencing, and at the single-cell level, by RNA-FISH, and is not attributable to differences in repressive histone H3K9me3 or H3K27me3 levels. Treatment with the DNA demethylating agent 5-deoxy-azacytidine does not increase Xi expression ahead of reprograming, but instead reveals a second cadre of genes that only become susceptible to reactivation upon induction of pluripotency. CONCLUSIONS: Collectively, these data not only underscore the multiple pathways that contribute to maintaining silencing along the human Xi chromosome but also suggest that transcriptional stochasticity among human cells could be useful for predicting and engineering epigenetic strategies to achieve locus-specific or domain-specific human Xi gene reactivation.
Cvetesic N, Lenhard B, 2017, Core promoters across the genome., Nat Biotechnol, Vol: 35, Pages: 123-124
Cheung N, Fung TK, Zeisig BB, et al., 2016, Targeting Aberrant Epigenetic Networks Mediated by PRMT1 and KDM4C in Acute Myeloid Leukemia, CANCER CELL, Vol: 29, Pages: 32-48, ISSN: 1535-6108
Cvetesic N, Dulic M, Bilus M, et al., 2016, Naturally Occurring Isoleucyl-tRNA Synthetase without tRNA-dependent Pre-transfer Editing, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 291, Pages: 8618-8631, ISSN: 0021-9258
Haberle V, Lenhard B, 2016, Promoter architectures and developmental gene regulation, SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, Vol: 57, Pages: 11-23, ISSN: 1084-9521
Kolder ICRM, van der Plas-Duivesteijn SJ, Tan G, et al., 2016, A full-body transcriptome and proteome resource for the European common carp, BMC GENOMICS, Vol: 17, ISSN: 1471-2164
Mathelier A, Fornes O, Arenillas DJ, et al., 2016, JASPAR 2016: a major expansion and update of the open-access database of transcription factor binding profiles, NUCLEIC ACIDS RESEARCH, Vol: 44, Pages: D110-D115, ISSN: 0305-1048
Nepal C, Coolen M, Hadzhiev Y, et al., 2016, Transcriptional, post-transcriptional and chromatin-associated regulation of pri-miRNAs, pre-miRNAs and moRNAs, NUCLEIC ACIDS RESEARCH, Vol: 44, Pages: 3070-3081, ISSN: 0305-1048
Tan G, Lenhard B, 2016, TFBSTools: an R/bioconductor package for transcription factor binding site analysis, BIOINFORMATICS, Vol: 32, Pages: 1555-1556, ISSN: 1367-4803
Adlakha AG, Armstrong-James DPH, Lenhard B, 2015, CALCINEURIN INHIBITION IMPAIRS PHENOTYPIC MATURATION OF DENDRITIC CELLS IN A IN VITRO MODEL OF INVASIVE ASPERGILLOSIS IN LUNG TRANSPLANT RECIPIENTS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A48-A49, ISSN: 0040-6376
Danks GB, Raasholm M, Campsteijn C, et al., 2015, Trans-Splicing and Operons in Metazoans: Translational Control in Maternally Regulated Development and Recovery from Growth Arrest, MOLECULAR BIOLOGY AND EVOLUTION, Vol: 32, Pages: 585-599, ISSN: 0737-4038
Haberle V, Forrest ARR, Hayashizaki Y, et al., 2015, CAGEr: precise TSS data retrieval and high-resolution promoterome mining for integrative analyses, NUCLEIC ACIDS RESEARCH, Vol: 43, ISSN: 0305-1048
Harmston N, Barešić A, Lenhard B, 2015, Correction to 'The mystery of extreme non-coding conservation'.
Harmston N, Ing-Simmons E, Perry M, et al., 2015, GenomicInteractions: An R/Bioconductor package for manipulating and investigating chromatin interaction data, BMC GENOMICS, Vol: 16, ISSN: 1471-2164
Ing-Simmons E, Seitan VC, Faure AJ, et al., 2015, Spatial enhancer clustering and regulation of enhancer-proximal genes by cohesin, GENOME RESEARCH, Vol: 25, Pages: 504-513, ISSN: 1088-9051
Ishibashi M, Manning E, Shoubridge C, et al., 2015, Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene, HUMAN GENETICS, Vol: 134, Pages: 1163-1182, ISSN: 0340-6717
Naville M, Ishibashi M, Ferg M, et al., 2015, Long-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome, NATURE COMMUNICATIONS, Vol: 6, ISSN: 2041-1723
Stadhouders R, Cico A, Stephen T, et al., 2015, Control of developmentally primed erythroid genes by combinatorial co-repressor actions, NATURE COMMUNICATIONS, Vol: 6, ISSN: 2041-1723
Andersson R, Gebhard C, Miguel-Escalada I, et al., 2014, An atlas of active enhancers across human cell types and tissues., Nature, Vol: 507, Pages: 455-461
Enhancers control the correct temporal and cell-type-specific activation of gene expression in multicellular eukaryotes. Knowing their properties, regulatory activity and targets is crucial to understand the regulation of differentiation and homeostasis. Here we use the FANTOM5 panel of samples, covering the majority of human tissues and cell types, to produce an atlas of active, in vivo-transcribed enhancers. We show that enhancers share properties with CpG-poor messenger RNA promoters but produce bidirectional, exosome-sensitive, relatively short unspliced RNAs, the generation of which is strongly related to enhancer activity. The atlas is used to compare regulatory programs between different cells at unprecedented depth, to identify disease-associated regulatory single nucleotide polymorphisms, and to classify cell-type-specific and ubiquitous enhancers. We further explore the utility of enhancer redundancy, which explains gene expression strength rather than expression patterns. The online FANTOM5 enhancer atlas represents a unique resource for studies on cell-type-specific enhancers and gene regulation.
Haberle V, Li N, Hadzhiev Y, et al., 2014, Two independent transcription initiation codes overlap on vertebrate core promoters, NATURE, Vol: 507, Pages: 381-+, ISSN: 0028-0836
Mathelier A, Zhao X, Zhang AW, et al., 2014, JASPAR 2014: an extensively expanded and updated open-access database of transcription factor binding profiles, NUCLEIC ACIDS RESEARCH, Vol: 42, Pages: D142-D147, ISSN: 0305-1048
Pascarella G, Lazarevic D, Plessy C, et al., 2014, NanoCAGE analysis of the mouse olfactory epithelium identifies the expression of vomeronasal receptors and of proximal LINE elements., Front Cell Neurosci, Vol: 8
By coupling laser capture microdissection to nanoCAGE technology and next-generation sequencing we have identified the genome-wide collection of active promoters in the mouse Main Olfactory Epithelium (MOE). Transcription start sites (TSSs) for the large majority of Olfactory Receptors (ORs) have been previously mapped increasing our understanding of their promoter architecture. Here we show that in our nanoCAGE libraries of the mouse MOE we detect a large number of tags mapped in loci hosting Type-1 and Type-2 Vomeronasal Receptors genes (V1Rs and V2Rs). These loci also show a massive expression of Long Interspersed Nuclear Elements (LINEs). We have validated the expression of selected receptors detected by nanoCAGE with in situ hybridization, RT-PCR and qRT-PCR. This work extends the repertory of receptors capable of sensing chemical signals in the MOE, suggesting intriguing interplays between MOE and VNO for pheromone processing and positioning transcribed LINEs as candidate regulatory RNAs for VRs expression.
Sharma Y, Chilamakuri CSR, Bakke M, et al., 2014, Computational Characterization of Modes of Transcriptional Regulation of Nuclear Receptor Genes, PLOS ONE, Vol: 9, ISSN: 1932-6203
Stadhouders R, Aktuna S, Thongjuea S, et al., 2014, HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers, JOURNAL OF CLINICAL INVESTIGATION, Vol: 124, Pages: 1699-1710, ISSN: 0021-9738
Zuin J, Franke V, van Ijcken WF, et al., 2014, A cohesin-independent role for NIPBL at promoters provides insights in CdLS., PLoS Genet, Vol: 10
The cohesin complex is crucial for chromosome segregation during mitosis and has recently also been implicated in transcriptional regulation and chromatin architecture. The NIPBL protein is required for the loading of cohesin onto chromatin, but how and where cohesin is loaded in vertebrate cells is unclear. Heterozygous mutations of NIPBL were found in 50% of the cases of Cornelia de Lange Syndrome (CdLS), a human developmental syndrome with a complex phenotype. However, no defects in the mitotic function of cohesin have been observed so far and the links between NIPBL mutations and the observed developmental defects are unclear. We show that NIPBL binds to chromatin in somatic cells with a different timing than cohesin. Further, we observe that high-affinity NIPBL binding sites localize to different regions than cohesin and almost exclusively to the promoters of active genes. NIPBL or cohesin knockdown reduce transcription of these genes differently, suggesting a cohesin-independent role of NIPBL for transcription. Motif analysis and comparison to published data show that NIPBL co-localizes with a specific set of other transcription factors. In cells derived from CdLS patients NIPBL binding levels are reduced and several of the NIPBL-bound genes have previously been observed to be mis-expressed in CdLS. In summary, our observations indicate that NIPBL mutations might cause developmental defects in different ways. First, defects of NIPBL might lead to cohesin-loading defects and thereby alter gene expression and second, NIPBL deficiency might affect genes directly via its role at the respective promoters.
Armant O, März M, Schmidt R, et al., 2013, Genome-wide, whole mount in situ analysis of transcriptional regulators in zebrafish embryos., Dev Biol, Vol: 380, Pages: 351-362
Transcription is the primary step in the retrieval of genetic information. A substantial proportion of the protein repertoire of each organism consists of transcriptional regulators (TRs). It is believed that the differential expression and combinatorial action of these TRs is essential for vertebrate development and body homeostasis. We mined the zebrafish genome exhaustively for genes encoding TRs and determined their expression in the zebrafish embryo by sequencing to saturation and in situ hybridisation. At the evolutionary conserved phylotypic stage, 75% of the 3302 TR genes encoded in the genome are already expressed. The number of expressed TR genes increases only marginally in subsequent stages and is maintained during adulthood suggesting important roles of the TR genes in body homeostasis. Fewer than half of the TR genes (45%, n=1711 genes) are expressed in a tissue-restricted manner in the embryo. Transcripts of 207 genes were detected in a single tissue in the 24h embryo, potentially acting as regulators of specific processes. Other TR genes were expressed in multiple tissues. However, with the exception of certain territories in the nervous system, we did not find significant synexpression suggesting that most tissue-restricted TRs act in a freely combinatorial fashion. Our data indicate that elaboration of body pattern and function from the phylotypic stage onward relies mostly on redeployment of TRs and post-transcriptional processes.
Carvalho RH, Hou J, Haberle V, et al., 2013, Genomewide DNA methylation analysis identifies novel methylated genes in non-small-cell lung carcinomas., J Thorac Oncol, Vol: 8, Pages: 562-573
INTRODUCTION: DNA methylation is part of the epigenetic regulatory mechanism present in all normal cells. It is tissue-specific and stably maintained throughout development, but often abnormally changed in cancer. Non-small-cell lung carcinoma (NSCLC) is the most deadly type of cancer, involving different tumor subtypes. This heterogeneity is a challenge for correct diagnosis and patient treatment. The stability and specificity make of DNA methylation a very suitable marker for epigenetic phenotyping of tumors. METHODS: To identify candidate markers for use in NSCLC diagnosis, we used genomewide DNA methylation maps that we had previously generated by MethylCap and next-generation sequencing and listed the most significant differentially methylated regions (DMRs). The 25 DMRs with highest significance in their methylation scores were selected. The methylation status of these DMRs was investigated in 61 tumors and matching control lung tissues by methylation-specific polymerase chain reaction. RESULTS: We found 12 novel DMRs that showed significant differences between tumor and control lung tissues. We also identified three novel DMRs for each of the two most common NSCLC subtypes, adenocarcinomas and squamous cell carcinomas. We propose a panel of five DMRs, composed of novel and known markers that exhibit high specificity and sensitivity to distinguish tumors from control lung tissues. CONCLUSION: Novel markers will aid the development of a highly specific epigenetic panel for accurate identification and subtyping of NSCLC tumors.
Danks G, Campsteijn C, Parida M, et al., 2013, OikoBase: a genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica, NUCLEIC ACIDS RESEARCH, Vol: 41, Pages: D845-D853, ISSN: 0305-1048
Frangini A, Sjoeberg M, Roman-Trufero M, et al., 2013, The Aurora B Kinase and the Polycomb Protein Ring1B Combine to Regulate Active Promoters in Quiescent Lymphocytes, MOLECULAR CELL, Vol: 51, Pages: 647-661, ISSN: 1097-2765
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