165 results found
Polychronopoulos D, King JWD, Nash AJ, et al., 2017, Conserved non-coding elements: developmental gene regulation meets genome organization., Nucleic Acids Research, Vol: 45, Pages: 12611-12624, ISSN: 0305-1048
Comparative genomics has revealed a class of non-protein-coding genomic sequences that display an extraordinary degree of conservation between two or more organisms, regularly exceeding that found within protein-coding exons. These elements, collectively referred to as conserved non-coding elements (CNEs), are non-randomly distributed across chromosomes and tend to cluster in the vicinity of genes with regulatory roles in multicellular development and differentiation. CNEs are organized into functional ensembles called genomic regulatory blocks-dense clusters of elements that collectively coordinate the expression of shared target genes, and whose span in many cases coincides with topologically associated domains. CNEs display sequence properties that set them apart from other sequences under constraint, and have recently been proposed as useful markers for the reconstruction of the evolutionary history of organisms. Disruption of several of these elements is known to contribute to diseases linked with development, and cancer. The emergence, evolutionary dynamics and functions of CNEs still remain poorly understood, and new approaches are required to enable comprehensive CNE identification and characterization. Here, we review current knowledge and identify challenges that need to be tackled to resolve the impasse in understanding extreme non-coding conservation.
Lenhard B, Siriboonpiputtana T, So CWE, 2017, Transcriptional memory of cells of origin overrides β‐catenin requirement of MLL cancer stem cells, EMBO Journal, ISSN: 0261-4189
While β‐catenin has been demonstrated as an essential molecule and therapeutic target for various cancer stem cells (CSCs) including those driven by MLL fusions, here we show that transcriptional memory from cells of origin predicts AML patient survival and allows β‐catenin‐independent transformation in MLL‐CSCs derived from hematopoietic stem cell (HSC)‐enriched LSK population but not myeloid–granulocyte progenitors. Mechanistically, β‐catenin regulates expression of downstream targets of a key transcriptional memory gene, Hoxa9 that is highly enriched in LSK‐derived MLL‐CSCs and helps sustain leukemic self‐renewal. Suppression of Hoxa9 sensitizes LSK‐derived MLL‐CSCs to β‐catenin inhibition resulting in abolishment of CSC transcriptional program and transformation ability. In addition, further molecular and functional analyses identified Prmt1 as a key common downstream mediator for β‐catenin/Hoxa9 functions in LSK‐derived MLL‐CSCs. Together, these findings not only uncover an unexpectedly important role of cells of origin transcriptional memory in regulating CSC self‐renewal, but also reveal a novel molecular network mediated by β‐catenin/Hoxa9/Prmt1 in governing leukemic self‐renewal.
Harmston N, Ing-Simmons E, Tan G, et al., 2017, Topologically associating domains are ancient features that coincide with Metazoan clusters of extreme noncoding conservation., Nature Communications, Vol: 8, ISSN: 2041-1723
Developmental genes in metazoan genomes are surrounded by dense clusters of conserved noncoding elements (CNEs). CNEs exhibit unexplained extreme levels of sequence conservation, with many acting as developmental long-range enhancers. Clusters of CNEs define the span of regulatory inputs for many important developmental regulators and have been described previously as genomic regulatory blocks (GRBs). Their function and distribution around important regulatory genes raises the question of how they relate to 3D conformation of these loci. Here, we show that clusters of CNEs strongly coincide with topological organisation, predicting the boundaries of hundreds of topologically associating domains (TADs) in human and Drosophila. The set of TADs that are associated with high levels of noncoding conservation exhibit distinct properties compared to TADs devoid of extreme noncoding conservation. The close correspondence between extreme noncoding conservation and TADs suggests that these TADs are ancient, revealing a regulatory architecture conserved over hundreds of millions of years.Metazoan genomes contain many clusters of conserved noncoding elements. Here, the authors provide evidence that these clusters coincide with distinct topologically associating domains in humans and Drosophila, revealing a conserved regulatory genomic architecture.
Cvetesic N, Lenhard B, 2017, Core promoters across the genome, Nature Biotechnology, Vol: 35, Pages: 123-124, ISSN: 1546-1696
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 Biology, Vol: 18, ISSN: 1474-760X
BackgroundInactivation 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.ResultsWe 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.ConclusionsCollectively, 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.
Adlakha A, Armstrong-James DAJ, Lenhard B, 2016, CALCINEURIN INHIBITION IMPAIRS THE DENDRITIC CELL TRANSCRIPTIONAL RESPONSE TO ASPERGILLUS FUMIGATUS INFECTION IN LUNG TRANSPLANT RECIPIENTS, THORAX, Vol: 71, Pages: A1-A1, ISSN: 0040-6376
Kolder IC, 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
BACKGROUND: The common carp (Cyprinus carpio) is the oldest, most domesticated and one of the most cultured fish species for food consumption. Besides its economic importance, the common carp is also highly suitable for comparative physiological and disease studies in combination with the animal model zebrafish (Danio rerio). They are genetically closely related but offer complementary benefits for fundamental research, with the large body mass of common carp presenting possibilities for obtaining sufficient cell material for advanced transcriptome and proteome studies. RESULTS: Here we have used 19 different tissues from an F1 hybrid strain of the common carp to perform transcriptome analyses using RNA-Seq. For a subset of the tissues we also have performed deep proteomic studies. As a reference, we updated the European common carp genome assembly using low coverage Pacific Biosciences sequencing to permit high-quality gene annotation. These annotated gene lists were linked to zebrafish homologs, enabling direct comparisons with published datasets. Using clustering, we have identified sets of genes that are potential selective markers for various types of tissues. In addition, we provide a script for a schematic anatomical viewer for visualizing organ-specific expression data. CONCLUSIONS: The identified transcriptome and proteome data for carp tissues represent a useful resource for further translational studies of tissue-specific markers for this economically important fish species that can lead to new markers for organ development. The similarity to zebrafish expression patterns confirms the value of common carp as a resource for studying tissue-specific expression in cyprinid fish. The availability of the annotated gene set of common carp will enable further research with both applied and fundamental purposes.
Adlakha A, Armstrong-James DPH, Lenhard B, 2016, The role of calcineurin inhibition in the dendritic cell response to Aspergillus fumigatus infection in lung transplant recipients, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: S371-S371, ISSN: 0041-1337
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: 1083-351X
Adlakha A, Armstrong-James D, Lenhard B, 2016, Effect of calcineurin inhibition on phenotypic maturation of dendritic cells in an in-vitro model of invasive aspergillosis in lung transplant recipients, Spring Meeting on Clinician Scientists in Training, Publisher: ELSEVIER SCIENCE INC, Pages: 16-16, ISSN: 0140-6736
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
The ability to efficiently investigate transcription factor binding sites (TFBSs) genome-wide is central to computational studies of gene regulation. TFBSTools is an R/Bioconductor package for the analysis and manipulation of TFBSs and their associated transcription factor profile matrices. TFBStools provides a toolkit for handling TFBS profile matrices, scanning sequences and alignments including whole genomes, and querying the JASPAR database. The functionality of the package can be easily extended to include advanced statistical analysis, data visualization and data integration. AVAILABILITY AND IMPLEMENTATION: The package is implemented in R and available under GPL-2 license from the Bioconductor website (http://bioconductor.org/packages/TFBSTools/). CONTACT: firstname.lastname@example.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Haberle V, Lenhard B, 2016, Promoter architectures and developmental gene regulation., Seminars in Cell & Developmental Biology, Vol: 57, Pages: 11-23, ISSN: 1096-3634
Core promoters are minimal regions sufficient to direct accurate initiation of transcription and are crucial for regulation of gene expression. They are highly diverse in terms of associated core promoter motifs, underlying sequence composition and patterns of transcription initiation. Distinctive features of promoters are also seen at the chromatin level, including nucleosome positioning patterns and presence of specific histone modifications. Recent advances in identifying and characterizing promoters using next-generation sequencing-based technologies have provided the basis for their classification into functional groups and have shed light on their modes of regulation, with important implications for transcriptional regulation in development. This review discusses the methodology and the results of genome-wide studies that provided insight into the diversity of RNA polymerase II promoter architectures in vertebrates and other Metazoa, and the association of these architectures with distinct modes of regulation in embryonic development and differentiation.
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: 1878-3686
Transcriptional deregulation plays a major role in acute myeloid leukemia, and therefore identification of epigenetic modifying enzymes essential for the maintenance of oncogenic transcription programs holds the key to better understanding of the biology and designing effective therapeutic strategies for the disease. Here we provide experimental evidence for the functional involvement and therapeutic potential of targeting PRMT1, an H4R3 methyltransferase, in various MLL and non-MLL leukemias. PRMT1 is necessary but not sufficient for leukemic transformation, which requires co-recruitment of KDM4C, an H3K9 demethylase, by chimeric transcription factors to mediate epigenetic reprogramming. Pharmacological inhibition of KDM4C/PRMT1 suppresses transcription and transformation ability of MLL fusions and MOZ-TIF2, revealing a tractable aberrant epigenetic circuitry mediated by KDM4C and PRMT1 in acute leukemia.
Nepal C, Coolen M, Hadzhiev Y, et al., 2015, Transcriptional, post-transcriptional and chromatin-associated regulation of pri-miRNAs, pre-miRNAs and moRNAs, Nucleic Acids Research, Vol: 44, Pages: 3070-3081, ISSN: 1362-4962
MicroRNAs (miRNAs) play a major role in the post-transcriptional regulation of target genes, especially in development and differentiation. Our understanding about the transcriptional regulation of miRNA genes is limited by inadequate annotation of primary miRNA (pri-miRNA) transcripts. Here, we used CAGE-seq and RNA-seq to provide genome-wide identification of the pri-miRNA core promoter repertoire and its dynamic usage during zebrafish embryogenesis. We assigned pri-miRNA promoters to 152 precursor-miRNAs (pre-miRNAs), the majority of which were supported by promoter associated post-translational histone modifications (H3K4me3, H2A.Z) and RNA polymerase II (RNAPII) occupancy. We validated seven miR-9 pri-miRNAs by in situ hybridization and showed similar expression patterns as mature miR-9. In addition, processing of an alternative intronic promoter of miR-9–5 was validated by 5′ RACE PCR. Developmental profiling revealed a subset of pri-miRNAs that are maternally inherited. Moreover, we show that promoter-associated H3K4me3, H2A.Z and RNAPII marks are not only present at pri-miRNA promoters but are also specifically enriched at pre-miRNAs, suggesting chromatin level regulation of pre-miRNAs. Furthermore, we demonstrated that CAGE-seq also detects 3′-end processing of pre-miRNAs on Drosha cleavage site that correlates with miRNA-offset RNAs (moRNAs) production and provides a new tool for detecting Drosha processing events and predicting pre-miRNA processing by a genome-wide assay.
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
Hurst LD, Ghanbarian AT, Forrest ARR, et al., 2015, The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome., PLoS Biol, Vol: 13
X chromosomes are unusual in many regards, not least of which is their nonrandom gene content. The causes of this bias are commonly discussed in the context of sexual antagonism and the avoidance of activity in the male germline. Here, we examine the notion that, at least in some taxa, functionally biased gene content may more profoundly be shaped by limits imposed on gene expression owing to haploid expression of the X chromosome. Notably, if the X, as in primates, is transcribed at rates comparable to the ancestral rate (per promoter) prior to the X chromosome formation, then the X is not a tolerable environment for genes with very high maximal net levels of expression, owing to transcriptional traffic jams. We test this hypothesis using The Encyclopedia of DNA Elements (ENCODE) and data from the Functional Annotation of the Mammalian Genome (FANTOM5) project. As predicted, the maximal expression of human X-linked genes is much lower than that of genes on autosomes: on average, maximal expression is three times lower on the X chromosome than on autosomes. Similarly, autosome-to-X retroposition events are associated with lower maximal expression of retrogenes on the X than seen for X-to-autosome retrogenes on autosomes. Also as expected, X-linked genes have a lesser degree of increase in gene expression than autosomal ones (compared to the human/Chimpanzee common ancestor) if highly expressed, but not if lowly expressed. The traffic jam model also explains the known lower breadth of expression for genes on the X (and the Z of birds), as genes with broad expression are, on average, those with high maximal expression. As then further predicted, highly expressed tissue-specific genes are also rare on the X and broadly expressed genes on the X tend to be lowly expressed, both indicating that the trend is shaped by the maximal expression level not the breadth of expression per se. Importantly, a limit to the maximal expression level explains biased tissue of expression
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
How transcription factors (TFs) cooperate within large protein complexes to allow rapid modulation of gene expression during development is still largely unknown. Here we show that the key haematopoietic LIM-domain-binding protein-1 (LDB1) TF complex contains several activator and repressor components that together maintain an erythroid-specific gene expression programme primed for rapid activation until differentiation is induced. A combination of proteomics, functional genomics and in vivo studies presented here identifies known and novel co-repressors, most notably the ETO2 and IRF2BP2 proteins, involved in maintaining this primed state. The ETO2–IRF2BP2 axis, interacting with the NCOR1/SMRT co-repressor complex, suppresses the expression of the vast majority of archetypical erythroid genes and pathways until its decommissioning at the onset of terminal erythroid differentiation. Our experiments demonstrate that multimeric regulatory complexes feature a dynamic interplay between activating and repressing components that determines lineage-specific gene expression and cellular differentiation.
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
Background: Precise quantitative and spatiotemporal control of gene expression is necessary to ensure propercellular differentiation and the maintenance of homeostasis. The relationship between gene expression andthe spatial organisation of chromatin is highly complex, interdependent and not completely understood. Thedevelopment of experimental techniques to interrogate both the higher-order structure of chromatin and theinteractions between regulatory elements has recently lead to important insights on how gene expression iscontrolled. The ability to gain these and future insights is critically dependent on computational tools for theanalysis and visualisation of data produced by these techniques.Results and conclusion: We have developed GenomicInteractions, a freely available R/Bioconductor packagedesigned for processing, analysis and visualisation of data generated from various types of chromosomeconformation capture experiments. The package allows the easy annotation and summarisation of largegenome-wide datasets at both the level of individual interactions and sets of genomic features, and providesseveral different methods for interrogating and visualising this type of data. We demonstrate this package’sutility by showing example analyses performed on interaction datasets generated using Hi-C and ChIA-PET.
Mathelier A, Fornes O, Arenillas DJ, et al., 2015, 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: 1362-4962
JASPAR (http://jaspar.genereg.net) is an open-access database storing curated, non-redundant transcription factor (TF) binding profiles representing transcription factor binding preferences as position frequency matrices for multiple species in six taxonomic groups. For this 2016 release, we expanded the JASPAR CORE collection with 494 new TF binding profiles (315 in vertebrates, 11 in nematodes, 3 in insects, 1 in fungi and 164 in plants) and updated 59 profiles (58 in vertebrates and 1 in fungi). The introduced profiles represent an 83% expansion and 10% update when compared to the previous release. We updated the structural annotation of the TF DNA binding domains (DBDs) following a published hierarchical structural classification. In addition, we introduced 130 transcription factor flexible models trained on ChIP-seq data for vertebrates, which capture dinucleotide dependencies within TF binding sites. This new JASPAR release is accompanied by a new web tool to infer JASPAR TF binding profiles recognized by a given TF protein sequence. Moreover, we provide the users with a Ruby module complementing the JASPAR API to ease programmatic access and use of the JASPAR collection of profiles. Finally, we provide the JASPAR2016 R/Bioconductor data package with the data of this release.
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: 1432-1203
Protein-coding mutations in the transcriptionfactor-encoding gene ARX cause various forms of intellectualdisability (ID) and epilepsy. In contrast, variationsin surrounding non-coding sequences are correlated withmilder forms of non-syndromic ID and autism and hadsuggested the importance of ARX gene regulation in theetiology of these disorders. We compile data on severalnovel and some already identified patients with or withoutID that carry duplications of ARX genomic region and consider likely genetic mechanisms underlying theneurodevelopmental defects. We establish the long-rangeregulatory domain of ARX and identify its brain regionspecificautoregulation. We conclude that neurodevelopmentaldisturbances in the patients may not simply arisefrom increased dosage due to ARX duplication. This isfurther exemplified by a small duplication involving a nonfunctionalARX copy, but with duplicated enhancers. ARXenhancers are located within a 504-kb region and regulateexpression specifically in the forebrain in developing andadult zebrafish. Transgenic enhancer-reporter lines wereused as in vivo tools to delineate a brain region-specific negative and positive autoregulation of ARX. We findautorepression of ARX in the telencephalon and autoactivationin the ventral thalamus. Fluorescently labeled brainregions in the transgenic lines facilitated the identificationof neuronal outgrowth and pathfinding disturbances in theventral thalamus and telencephalon that occur when arxadosage is diminished. In summary, we have established amodel for how breakpoints in long-range gene regulationalter the expression levels of a target gene brain regionspecifically,and how this can cause subtle neuronal phenotypesrelating to the etiology of associated neuropsychiatricdisease.
Harmston N, Baresic A, Lenhard B, 2015, The mystery of extreme non-coding conservation (vol 368, 20130021, 2013), Publisher: ROYAL SOC
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
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
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
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
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
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-+, ISSN: 0028-0836
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
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, FRONTIERS IN CELLULAR NEUROSCIENCE, Vol: 8
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