Dissecting microregulation of a master regulatory network

<p>Abstract</p> <p>Background</p> <p>The master regulator p53 tumor-suppressor protein through coordination of several downstream target genes and upstream transcription factors controls many pathways important for tumor suppression. While it has been reported that some of the p53's functions are microRNA-mediated, it is not known as to how many other microRNAs might contribute to the p53-mediated tumorigenesis.</p> <p>Results</p> <p>Here, we use bioinformatics-based integrative approach to identify and prioritize putative p53-regulated miRNAs, and unravel the miRNA-based microregulation of the p53 master regulatory network. Specifically, we identify putative microRNA regulators of a) transcription factors that are upstream or downstream to p53 and b) p53 interactants. The putative <it>p53-miRs </it>and their targets are prioritized using current knowledge of cancer biology and literature-reported cancer-miRNAs.</p> <p>Conclusion</p> <p>Our predicted p53-miRNA-gene networks strongly suggest that coordinated transcriptional and <it>p53-miR </it>mediated networks could be integral to tumorigenesis and the underlying processes and pathways.</p

eXframe: reusable framework for storage, analysis and visualization of genomics experiments

<p>Abstract</p> <p>Background</p> <p>Genome-wide experiments are routinely conducted to measure gene expression, DNA-protein interactions and epigenetic status. Structured metadata for these experiments is imperative for a complete understanding of experimental conditions, to enable consistent data processing and to allow retrieval, comparison, and integration of experimental results. Even though several repositories have been developed for genomics data, only a few provide annotation of samples and assays using controlled vocabularies. Moreover, many of them are tailored for a single type of technology or measurement and do not support the integration of multiple data types.</p> <p>Results</p> <p>We have developed eXframe - a reusable web-based framework for genomics experiments that provides 1) the ability to publish structured data compliant with accepted standards 2) support for multiple data types including microarrays and next generation sequencing 3) query, analysis and visualization integration tools (enabled by consistent processing of the raw data and annotation of samples) and is available as open-source software. We present two case studies where this software is currently being used to build repositories of genomics experiments - one contains data from hematopoietic stem cells and another from Parkinson's disease patients.</p> <p>Conclusion</p> <p>The web-based framework eXframe offers structured annotation of experiments as well as uniform processing and storage of molecular data from microarray and next generation sequencing platforms. The framework allows users to query and integrate information across species, technologies, measurement types and experimental conditions. Our framework is reusable and freely modifiable - other groups or institutions can deploy their own custom web-based repositories based on this software. It is interoperable with the most important data formats in this domain. We hope that other groups will not only use eXframe, but also contribute their own useful modifications.</p

iCanPlot: Visual Exploration of High-Throughput Omics Data Using Interactive Canvas Plotting

Increasing use of high throughput genomic scale assays requires effective visualization and analysis techniques to facilitate data interpretation. Moreover, existing tools often require programming skills, which discourages bench scientists from examining their own data. We have created iCanPlot, a compelling platform for visual data exploration based on the latest technologies. Using the recently adopted HTML5 Canvas element, we have developed a highly interactive tool to visualize tabular data and identify interesting patterns in an intuitive fashion without the need of any specialized computing skills. A module for geneset overlap analysis has been implemented on the Google App Engine platform: when the user selects a region of interest in the plot, the genes in the region are analyzed on the fly. The visualization and analysis are amalgamated for a seamless experience. Further, users can easily upload their data for analysis—which also makes it simple to share the analysis with collaborators. We illustrate the power of iCanPlot by showing an example of how it can be used to interpret histone modifications in the context of gene expression

Genomes of the human filarial parasites Mansonella perstans and Mansonella ozzardi

Funding Information: Research funding was provided by New England Biolabs, Ipswich, MA 01938, USA to AS, ZL, LE, RM, CP, CC. FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo) supported the field research in Brazil through a research grant to M.U.F (2013/12723-7) and a doctoral scholarship to NL (2013/26928-0). Acknowledgments Funding Information: Research funding was provided by New England Biolabs, Ipswich, MA 01938, USA to AS, ZL, LE, RM, CP, CC. FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo) supported the field research in Brazil through a research grant to M.U.F (2013/12723-7) and a doctoral scholarship to NL (2013/26928-0). Publisher Copyright: Copyright © 2023 Sinha, Li, Poole, Morgan, Ettwiller, Lima, Ferreira, Fombad, Wanji and Carlow.The filarial parasites Mansonella ozzardi and Mansonella perstans, causative agents of mansonellosis, infect hundreds of millions of people worldwide, yet remain among the most understudied of the human filarial pathogens. M. ozzardi is highly prevalent in Latin American countries and Caribbean Islands, while M. perstans is predominantly found in sub-Saharan Africa as well as in a few areas in South America. In addition to the differences in their geographical distribution, the two parasites are transmitted by different insect vectors, as well as exhibit differences in their responses to commonly used anthelminthic drugs. The lack of genome information has hindered investigations into the biology and evolution of Mansonella parasites and understanding the molecular basis of the clinical differences between species. In the current study, high quality genomes of two independent clinical isolates of M. perstans from Cameroon and two M. ozzardi isolates one from Brazil and one from Venezuela are reported. The genomes are approximately 76 Mb in size, encode about 10,000 genes each, and are largely complete based on BUSCO scores of about 90%, similar to other completed filarial genomes. These sequences represent the first genomes from Mansonella parasites and enabled a comparative genomic analysis of the similarities and differences between Mansonella and other filarial parasites. Horizontal DNA transfers (HDT) from mitochondria (nuMTs) as well as transfers from genomes of endosymbiotic Wolbachia bacteria (nuWTs) to the host nuclear genome were identified and analyzed. Sequence comparisons and phylogenetic analysis of known targets of anti-filarial drugs diethylcarbamazine (DEC), ivermectin and mebendazole revealed that all known target genes were present in both species, except for the DEC target encoded by gon-2 gene, which is fragmented in genome assemblies from both M. ozzardi isolates. These new reference genome sequences will provide a valuable resource for further studies on biology, symbiosis, evolution and drug discovery.publishersversionpublishe

MLL-rearranged B lymphoblastic leukemias selectively express the immunoregulatory carbohydrate-binding protein galectin-1

Leukemias with 11q23 translocations involving the Mixed Lineage Leukemia (MLL) gene exhibit unique clinical and biological features and have a poor prognosis. In a screen for molecular markers of MLL rearrangement, we identified the specific overexpression of an immunomodulatory lectin Galectin-1 (Gal1) in MLL-rearranged B lymphoblastic leukemias (B-ALL) compared to other MLL-germline ALLs. To assess the diagnostic utility of Gal1 expression in identifying MLL-rearranged B-ALLs, we performed Gal1 immunostaining on a large series of primary ALLs with known MLL status. All 11 MLL-rearranged B-ALLs had abundant Gal1 expression; in marked contrast, only 1 of 42 germline-MLL B-ALLs expressed Gal1. In addition, Gal1 was readily detected in diagnostic samples of MLL-rearranged B-ALLs by intracellular flow cytometry. Since deregulated gene expression in MLL-rearranged leukemias may be related to the altered histone methyltransferase activity of MLL fusion protein complex, we analyzed histone H3 lysine 79 (H3K79) dimethylation in the Gal1 promoter region using chromatin immunoprecipitation. Gal1 promoter H3K79diMe was ≈ 5 fold higher in a MLL-rearranged B-ALL cell line than in a B-ALL line without the MLL translocation. Furthermore, the Gal1 promoter H3K79 was significantly hypermethylated in primary MLL-rearranged B-ALLs compared to MLL-germline B-ALLs and normal pre-B cells, implicating this epigenetic modification as a mechanism for Gal1 overexpression in MLL B-ALL.Fil: Juszczynski, Przemyslaw. Dana Farber Cancer Institute; Estados UnidosFil: Rodig, Scott J.. Brigham & Women; Estados UnidosFil: Ouyang, Jing. Dana Farber Cancer Institute; Estados UnidosFil: O´Donnell, Evan. Dana Farber Cancer Institute; Estados UnidosFil: Takeyama, Kunihiko. Dana Farber Cancer Institute; Estados UnidosFil: Mlynarski, Wojciech. Dana Farber Cancer Institute; Estados UnidosFil: Mycko, Katarzyna. Dana Farber Cancer Institute; Estados UnidosFil: Szczepanski, Tomasz. Dana Farber Cancer Institute; Estados UnidosFil: Gaworczyk, Anna. Medical University of Lodz; PoloniaFil: Krivtsov, Andrei. Medical University of Lodz; PoloniaFil: Faber, Joerg. Medical University of Silesia; PoloniaFil: Sinha, Amit U.. Medical University of Lublin; PoloniaFil: Rabinovich, Gabriel Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Armstrong, Scott A.. Children; Estados UnidosFil: Kutok, Jeffery. Children; Estados UnidosFil: Shipp, Margaret A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentin

Mutations in epigenetic regulators including SETD2 are gained during relapse in pediatric acute lymphoblastic leukemia

Relapsed pediatric acute lymphoblastic leukemia (ALL) has high rates of treatment failure. Epigenetic regulators have been proposed as modulators of chemoresistance, here we sequence genes encoding epigenetic regulators in matched diagnosis-remission-relapse ALL samples. We find significant enrichment of mutations in epigenetic regulators at relapse with recurrent somatic mutations in SETD2, CREBBP, MSH6, KDM6A and MLL2, mutations in signaling factors are not enriched. Somatic alterations in SETD2, including frameshift and nonsense mutations, are present at 12% in a large de novo ALL patient cohort. We conclude that the enrichment of mutations in epigenetic regulators at relapse is consistent with a role in mediating therapy resistance

Cinteny: flexible analysis and visualization of synteny and genome rearrangements in multiple organisms

BACKGROUND: Identifying syntenic regions, i.e., blocks of genes or other markers with evolutionary conserved order, and quantifying evolutionary relatedness between genomes in terms of chromosomal rearrangements is one of the central goals in comparative genomics. However, the analysis of synteny and the resulting assessment of genome rearrangements are sensitive to the choice of a number of arbitrary parameters that affect the detection of synteny blocks. In particular, the choice of a set of markers and the effect of different aggregation strategies, which enable coarse graining of synteny blocks and exclusion of micro-rearrangements, need to be assessed. Therefore, existing tools and resources that facilitate identification, visualization and analysis of synteny need to be further improved to provide a flexible platform for such analysis, especially in the context of multiple genomes. RESULTS: We present a new tool, Cinteny, for fast identification and analysis of synteny with different sets of markers and various levels of coarse graining of syntenic blocks. Using Hannenhalli-Pevzner approach and its extensions, Cinteny also enables interactive determination of evolutionary relationships between genomes in terms of the number of rearrangements (the reversal distance). In particular, Cinteny provides: i) integration of synteny browsing with assessment of evolutionary distances for multiple genomes; ii) flexibility to adjust the parameters and re-compute the results on-the-fly; iii) ability to work with user provided data, such as orthologous genes, sequence tags or other conserved markers. In addition, Cinteny provides many annotated mammalian, invertebrate and fungal genomes that are pre-loaded and available for analysis at . CONCLUSION: Cinteny allows one to automatically compare multiple genomes and perform sensitivity analysis for synteny block detection and for the subsequent computation of reversal distances. Cinteny can also be used to interactively browse syntenic blocks conserved in multiple genomes, to facilitate genome annotation and validation of assemblies for newly sequenced genomes, and to construct and assess phylogenomic trees

Estimation of reactive inorganic iodine fluxes in the Indian and Southern Ocean marine boundary layer

Iodine chemistry has noteworthy impacts on the oxidising capacity of the marine boundary layer (MBL) through the depletion of ozone (O3) and changes to HOx (OH=HO2) and NOx (NO=NO2) ratios. Hitherto, studies have shown that the reaction of atmospheric O3 with surface seawater iodide (I-) contributes to the flux of iodine species into the MBL mainly as hypoiodous acid (HOI) and molecular iodine (I2). Here, we present the first concomitant observations of iodine oxide (IO), O3 in the gas phase, and sea surface iodide concentrations. The results from three field campaigns in the Indian Ocean and the Southern Ocean during 2015 2017 are used to compute reactive iodine fluxes in the MBL. Observations of atmospheric IO by multi-axis differential optical absorption spectroscopy (MAX-DOAS) show active iodine chemistry in this environment, with IO values up to 1 pptv (parts per trillion by volume) below latitudes of 40° S. In order to compute the sea-to-air iodine flux supporting this chemistry, we compare previously established global sea surface iodide parameterisations with new regionspecific parameterisations based on the new iodide observations. This study shows that regional changes in salinity and sea surface temperature play a role in surface seawater iodide estimation. Sea air fluxes of HOI and I2, calculated from the atmospheric ozone and seawater iodide concentrations (observed and predicted), failed to adequately explain the detected IO in this region. This discrepancy highlights the need to measure direct fluxes of inorganic and organic iodine species in the marine environment. Amongst other potential drivers of reactive iodine chemistry investigated, chlorophyll a showed a significant correlation with atmospheric IO (R D 0:7 above the 99 % significance level) to the north of the polar front. This correlation might be indicative of a biogenic control on iodine sources in this region

Mapping 123 million neonatal, infant and child deaths between 2000 and 2017

Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2—to end preventable child deaths by 2030—we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000–2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations