152 results found
Merkenschlager M, Ferreirós-Vidal I, Carroll T, et al., Feedforward regulation of Myc coordinates lineage-specific with housekeeping gene expression during B cell progenitor cell differentiation, PLoS Biology, ISSN: 1544-9173
The differentiation of self-renewingprogenitor cells requires not only the regulation of lineage-and developmental stage-specific genes, but also the coordinated adaptation of housekeeping functionsfrom a metabolically active, proliferative state towards quiescence. How metabolic and cell cycle states are coordinated with the regulation of cell type-specific genes is an important question, as dissociation between differentiation, cell cycle, and metabolic states is a hallmark of cancer. Here we use a model system to systematically identify key transcriptional regulators of Ikaros-dependent B cell progenitor differentiation. We find that the coordinated regulation of housekeeping functions and tissue-specific gene expressionrequires afeedforward circuit whereby Ikarosdownregulates the expression of Myc. Our findings show how coordination between differentiation and housekeeping statescan be achieved by interconnected regulators. Similar principles likely coordinate differentiation and housekeeping functions during progenitor cell differentiation in other cell lineages.
Tan G, Polychronopoulos D, Lenhard B, 2019, CNEr: a toolkit for exploring extreme noncoding conservation, Publisher: Cold Spring Harbor Laboratory
<jats:title>Abstract</jats:title><jats:p>Conserved Noncoding Elements (CNEs) are elements exhibiting extreme noncoding conservation in Metazoan genomes. They cluster around developmental genes and act as long-range enhancers, yet nothing that we know about their function explains the observed conservation levels. Clusters of CNEs coincide with topologically associating domains (TADs), indicating ancient origins and stability of TAD locations. This has suggested further hypotheses about the still elusive origin of CNEs, and has provided a comparative genomics-based method of estimating the position of TADs around developmentally regulated genes in genomes where chromatin conformation capture data is missing. To enable researchers in gene regulation and chromatin biology to start deciphering this phenomenon, we developed <jats:italic>CNEr</jats:italic>, a R/Bioconductor toolkit for large-scale identification of CNEs and for studying their genomic properties. We apply <jats:italic>CNEr</jats:italic> to two novel genome comparisons - fruit fly vs tsetse fly, and two sea urchin genomes - and report novel insights gained from their analysis. We also show how to reveal interesting characteristics of CNEs by coupling CNEr with existing Bioconductor packages. <jats:italic>CNEr</jats:italic> is available at Bioconductor (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://bioconductor.org/packages/CNEr/">https://bioconductor.org/packages/CNEr/</jats:ext-link>) and maintained at github (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://github.com/ge11232002/CNEr">https://github.com/ge11232002/CNEr</jats:ext-link>).</jats:p>
Borlin CS, Cvetesic N, Holland P, et al., 2019, Saccharomyces cerevisiae displays a stable transcription start site landscape in multiple conditions, FEMS YEAST RESEARCH, Vol: 19, ISSN: 1567-1356
CRISPR/Cas9 is a powerful genome-editing tool, but spurious off-target edits present a barrier to therapeutic applications. To understand how CRISPR/Cas9 discriminates between on-targets and off-targets, we have developed a single-molecule assay combining optical tweezers with fluorescence to monitor binding to λ-DNA. At low forces, the Streptococcus pyogenes Cas9 complex binds and cleaves DNA specifically. At higher forces, numerous off-target binding events appear repeatedly at the same off-target sites in a guide-RNA-sequence-dependent manner, driven by the mechanical distortion of the DNA. Using single-molecule Förster resonance energy transfer (smFRET) and cleavage assays, we show that DNA bubbles induce off-target binding and cleavage at these sites, even with ten mismatches, as well as at previously identified in vivo off-targets. We propose that duplex DNA destabilization during cellular processes (for example, transcription, replication, etc.) can expose these cryptic off-target sites to Cas9 activity, highlighting the need for improved off-target prediction algorithms.
Lenhard B, Sternberg MJE, 2019, Computation Resources for Molecular Biology: Special Issue 2019, Journal of Molecular Biology, ISSN: 0022-2836
Newton M, Taylor B, Driessen R, et al., DNA stretching induces Cas9 off-target binding and cleavage, Nature Structural and Molecular Biology, ISSN: 1545-9985
CRISPR/Cas9 is a powerful genome editing tool, but spurious off-target edits present a barrier towards therapeutic applications. To understand how CRISPR/Cas9 discrimi-nates between on- and off-targets, we have developed a single-molecule assay com-bining optical tweezers with fluorescence to monitor binding to λ-DNA. At low forces, the Streptococcus pyogenes Cas9 complex binds and cleaves DNA specifically. At higher forces, numerous off-target binding events appear repeatedly at the same off-target sites in a guide-RNA-sequence dependent manner, driven by the mechanical distortion of the DNA. Using single-molecule FRET and cleavage assays, we show that DNA bubbles induce off-target binding and cleavage at these sites, even with 10 mis-matches, as well as at previously identified in vivo off-targets. We propose that duplex DNA destabilization during cellular processes (e.g., transcription, replication, etc) can expose these cryptic off-target sites to Cas9 activity, highlighting the need for improved off-target prediction algorithms.
Nash AJ, Lenhard B, 2018, A Novel Measure of Non-coding Genome Conservation Identifies Genomic Regulatory Blocks Within Primates., Bioinformatics
Motivation: Clusters of extremely conserved non-coding elements (CNEs) mark genomic regions devoted to cis-regulation of key developmental genes in Metazoa. We have recently shown that their span coincides with that of topologically associating domains (TADs), making them useful for estimating conserved TAD boundaries in the absence of Hi-C data. The standard approach - detecting CNEs in genome alignments and then establishing the boundaries of their clusters - requires tuning of several parameters and breaks down when comparing closely related genomes. Results: We present a novel, kurtosis-based measure of pairwise non-coding conservation that requires no pre-set thresholds for conservation level and length of CNEs. We show that it performs robustly across a large span of evolutionary distances, including across the closely related genomes of primates for which standard approaches fail. The method is straightforward to implement and enables detection and comparison of clusters of CNEs and estimation of underlying TADs across a vastly increased range of Metazoan genomes. Supplementary information: Supplementary data are available at Bioinformatics online.
Marletaz F, Firbas PN, Maeso I, et al., 2018, Amphioxus functional genomics and the origins of vertebrate gene regulation, Nature, Vol: 564, Pages: 64-70, ISSN: 0028-0836
Vertebrates have greatly elaborated the basic chordate body plan and evolved highly distinctive genomes that have been sculpted by two whole-genome duplications. Here we sequence the genome of the Mediterranean amphioxus (Branchiostoma lanceolatum) and characterize DNA methylation, chromatin accessibility, histone modifications and transcriptomes across multiple developmental stages and adult tissues to investigate the evolution of the regulation of the chordate genome. Comparisons with vertebrates identify an intermediate stage in the evolution of differentially methylated enhancers, and a high conservation of gene expression and its cis-regulatory logic between amphioxus and vertebrates that occurs maximally at an earlier mid-embryonic phylotypic period. We analyse regulatory evolution after whole-genome duplications, and find that—in vertebrates—over 80% of broadly expressed gene families with multiple paralogues derived from whole-genome duplications have members that restricted their ancestral expression, and underwent specialization rather than subfunctionalization. Counter-intuitively, paralogues that restricted their expression increased the complexity of their regulatory landscapes. These data pave the way for a better understanding of the regulatory principles that underlie key vertebrate innovations.
Cvetesic N, Leitch HG, Borkowska M, et al., 2018, SLIC-CAGE: high-resolution transcription start site mapping using nanogram-levels of total RNA, Genome Research, ISSN: 1088-9051
Cap analysis of gene expression (CAGE) is a methodology for genome-wide quantitative mapping of mRNA 5′ ends to precisely capture transcription start sites at a single nucleotide resolution. In combination with high-throughput sequencing, CAGE has revolutionized our understanding of rules of transcription initiation, led to discovery of new core promoter sequence features and discovered transcription initiation at enhancers genome-wide. The biggest limitation of CAGE is that even the most recently improved version (nAnT-iCAGE) still requires large amounts of total cellular RNA (5 micrograms), preventing its application to scarce biological samples such as those from early embryonic development or rare cell types. Here, we present SLIC-CAGE, a Super-Low Input Carrier-CAGE approach to capture 5′ ends of RNA polymerase II transcripts from as little as 5-10 ng of total RNA. The dramatic increase in sensitivity is achieved by specially designed, selectively degradable carrier RNA. We demonstrate the ability of SLIC-CAGE to generate data for genome-wide promoterome with 1000-fold less material than required by existing CAGE methods by generating a complex, high quality library from mouse embryonic day (E) 11.5 primordial germ cells.
Merkenschlager M, Cuartero S, Weiss F, et al., 2018, Control of inducible gene expression links cohesin to hematopoietic progenitor self-renewal and differentiation, Nature Immunology, Vol: 19, Pages: 932-941, ISSN: 1529-2908
Cohesin is important for 3D genome organization. Nevertheless, even the complete removal of cohesin has surprisingly little impact on steady-state gene transcription and enhancer activity. Here we show that cohesin is required for the core transcriptional response of primary macrophages to microbial signals, and for inducible enhancer activity that underpins inflammatory gene expression. Consistent with a role for inflammatory signals in promoting myeloid differentiation of hematopoietic stem and progenitor cells (HPSCs), cohesin mutations in HSPCs led to reduced inflammatory gene expression and increased resistance to differentiation-inducing inflammatory stimuli. These findings uncover an unexpected dependence of inducible gene expression on cohesin, link cohesin with myeloid differentiation, and may help explain the prevalence of cohesin mutations in human acute myeloid leukemia.
Boerlin CS, Cvetesic N, Holland P, et al., 2018, Saccharomyces cerevisiae displays a stable transcription start site landscape in multiple conditions, Publisher: Cold Spring Harbor Laboratory
<jats:p>One of the fundamental processes that determine cellular fate is regulation of gene transcription. Understanding these regulatory processes is therefore essential for understanding cellular responses to changes in environmental conditions. At the core promoter, the regulatory region containing the transcription start site (TSS), all inputs regulating transcription are integrated. Here, we used Cap Analysis of Gene Expression (CAGE) to analyze the pattern of transcription start sites at four different environmental conditions (limited in ethanol, limited in nitrogen, limited in glucose and limited in glucose under anaerobic conditions) using the Saccharomyces cerevisiae strain CEN.PK113-7D. With this experimental setup we were able to show that the TSS landscape in yeast is stable at different metabolic states of the cell. We also show that the shape index, a characteristic feature of each TSS describing the spatial distribution of transcription initiation events, has a surprisingly strong negative correlation with the measured expression levels. Our analysis supplies a set of high quality TSS annotations useful for metabolic engineering and synthetic biology approaches in the industrially relevant laboratory strain CEN.PK113-7D, and provides novel insights into yeast TSS dynamics and gene regulation.</jats:p>
Lessel D, Gehbauer C, Bramswig NC, et al., 2018, BCL11B mutations in patients affected by a neurodevelopmental disorder with reduced type 2 innate lymphoid cells, BRAIN, Vol: 141, Pages: 2299-2311, ISSN: 0006-8950
Li C, Lenhard B, Luscombe NM, 2018, Integrated analysis sheds light on evolutionary trajectories of young transcription start sites in the human genome, Genome Research, Vol: 28, Pages: 676-688, ISSN: 1088-9051
Understanding the molecular mechanisms and evolution of the gene regulatory system remains a major challenge in biology. Transcription start sites (TSSs) are especially interesting because they are central to initiating gene expression. Previous studies revealed widespread transcription initiation and fast turnover of TSSs in mammalian genomes. Yet, how new TSSs originate and how they evolve over time remain poorly understood. To address these questions, we analyzed ∼200,000 human TSSs by integrating evolutionary (inter- and intra-species) and functional genomic data, particularly focusing on evolutionarily young TSSs that emerged in the primate lineage. TSSs were grouped according to their evolutionary age using sequence alignment information as a proxy. Comparisons of young and old TSSs revealed that (1) new TSSs emerge through a combination of intrinsic factors, like the sequence properties of transposable elements and tandem repeats, and extrinsic factors such as their proximity to existing regulatory modules; (2) new TSSs undergo rapid evolution that reduces the inherent instability of repeat sequences associated with a high propensity of TSS emergence; and (3) once established, the transcriptional competence of surviving TSSs is gradually enhanced, with evolutionary changes subject to temporal (fewer regulatory changes in younger TSSs) and spatial constraints (fewer regulatory changes in more isolated TSSs). These findings advance our understanding of how regulatory innovations arise in the genome throughout evolution and highlight the genomic robustness and evolvability in these processes.
Hill PWS, Leitch HG, Requena CE, et al., 2018, Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte, Nature, Vol: 555, Pages: 392-396, ISSN: 0028-0836
Gametes are highly specialized cells that can give rise to the next generation through their ability to generate a totipotent zygote. In mice, germ cells are first specified in the developing embryo around embryonic day (E) 6.25 as primordial germ cells (PGCs)1. Following subsequent migration into the developing gonad, PGCs undergo a wave of extensive epigenetic reprogramming around E10.5–E11.52,3,4,5,6,7,8,9,10,11, including genome-wide loss of 5-methylcytosine2,3,4,5,7,8,9,10,11. The underlying molecular mechanisms of this process have remained unclear, leading to our inability to recapitulate this step of germline development in vitro12,13,14. Here we show, using an integrative approach, that this complex reprogramming process involves coordinated interplay among promoter sequence characteristics, DNA (de)methylation, the polycomb (PRC1) complex and both DNA demethylation-dependent and -independent functions of TET1 to enable the activation of a critical set of germline reprogramming-responsive genes involved in gamete generation and meiosis. Our results also reveal an unexpected role for TET1 in maintaining but not driving DNA demethylation in gonadal PGCs. Collectively, our work uncovers a fundamental biological role for gonadal germline reprogramming and identifies the epigenetic principles of the PGC-to-gonocyte transition that will help to guide attempts to recapitulate complete gametogenesis in vitro.
Danks GB, Navratilova P, Lenhard B, et al., 2018, Distinct core promoter codes drive transcription initiation at key developmental transitions in a marine chordate, BMC Genomics, Vol: 19, ISSN: 1471-2164
BACKGROUND: Development is largely driven by transitions between transcriptional programs. The initiation of transcription at appropriate sites in the genome is a key component of this and yet few rules governing selection are known. Here, we used cap analysis of gene expression (CAGE) to generate bp-resolution maps of transcription start sites (TSSs) across the genome of Oikopleura dioica, a member of the closest living relatives to vertebrates. RESULTS: Our TSS maps revealed promoter features in common with vertebrates, as well as striking differences, and uncovered key roles for core promoter elements in the regulation of development. During spermatogenesis there is a genome-wide shift in mode of transcription initiation characterized by a novel core promoter element. This element was associated with > 70% of male-specific transcription, including the use of cryptic internal promoters within operons. In many cases this led to the exclusion of trans-splice sites, revealing a novel mechanism for regulating which mRNAs receive the spliced leader. Binding of the cell cycle regulator, E2F1, is enriched at the TSS of maternal genes in endocycling nurse nuclei. In addition, maternal promoters lack the TATA-like element found in zebrafish and have broad, rather than sharp, architectures with ordered nucleosomes. Promoters of ribosomal protein genes lack the highly conserved TCT initiator. We also report an association between DNA methylation on transcribed gene bodies and the TATA-box. CONCLUSIONS: Our results reveal that distinct functional promoter classes and overlapping promoter codes are present in protochordates like in vertebrates, but show extraordinary lineage-specific innovations. Furthermore, we uncover a genome-wide, developmental stage-specific shift in the mode of TSS selection. Our results provide a rich resource for the study of promoter structure and evolution in Metazoa.
Khan A, Fornes O, Stigliani A, et al., 2018, JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework (vol 46, pg 260, 2017), Publisher: OXFORD UNIV PRESS
Khan A, Fornes O, Stigliani A, et al., 2017, JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework., Nucleic Acids Research, Vol: 46, Pages: D260-D266, ISSN: 0305-1048
JASPAR (http://jaspar.genereg.net) is an open-access database of curated, non-redundant transcription factor (TF)-binding profiles stored as position frequency matrices (PFMs) and TF flexible models (TFFMs) for TFs across multiple species in six taxonomic groups. In the 2018 release of JASPAR, the CORE collection has been expanded with 322 new PFMs (60 for vertebrates and 262 for plants) and 33 PFMs were updated (24 for vertebrates, 8 for plants and 1 for insects). These new profiles represent a 30% expansion compared to the 2016 release. In addition, we have introduced 316 TFFMs (95 for vertebrates, 218 for plants and 3 for insects). This release incorporates clusters of similar PFMs in each taxon and each TF class per taxon. The JASPAR 2018 CORE vertebrate collection of PFMs was used to predict TF-binding sites in the human genome. The predictions are made available to the scientific community through a UCSC Genome Browser track data hub. Finally, this update comes with a new web framework with an interactive and responsive user-interface, along with new features. All the underlying data can be retrieved programmatically using a RESTful API and through the JASPAR 2018 R/Bioconductor package.
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: email@example.com 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.
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