Publications by authors named "Alex Dobin"

9 Publications

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Dynamics of microRNA expression during mouse prenatal development.

Genome Res 2019 11 23;29(11):1900-1909. Epub 2019 Oct 23.

Department of Developmental and Cell Biology, University of California Irvine, Irvine, California 92697, USA.

MicroRNAs (miRNAs) play a critical role as posttranscriptional regulators of gene expression. The ENCODE Project profiled the expression of miRNAs in an extensive set of organs during a time-course of mouse embryonic development and captured the expression dynamics of 785 miRNAs. We found distinct organ-specific and developmental stage-specific miRNA expression clusters, with an overall pattern of increasing organ-specific expression as embryonic development proceeds. Comparative analysis of conserved miRNAs in mouse and human revealed stronger clustering of expression patterns by organ type rather than by species. An analysis of messenger RNA expression clusters compared with miRNA expression clusters identifies the potential role of specific miRNA expression clusters in suppressing the expression of mRNAs specific to other developmental programs in the organ in which these miRNAs are expressed during embryonic development. Our results provide the most comprehensive time-course of miRNA expression as part of an integrated ENCODE reference data set for mouse embryonic development.
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http://dx.doi.org/10.1101/gr.248997.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836743PMC
November 2019

Gene-specific patterns of expression variation across organs and species.

Genome Biol 2016 07 8;17(1):151. Epub 2016 Jul 8.

Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona, 08003, Spain.

Background: A comparison of transcriptional profiles derived from different tissues in a given species or among different species assumes that commonalities reflect evolutionarily conserved programs and that differences reflect species or tissue responses to environmental conditions or developmental program staging. Apparently conflicting results have been published regarding whether organ-specific transcriptional patterns dominate over species-specific patterns, or vice versa, making it unclear to what extent the biology of a given organism can be extrapolated to another. These studies have in common that they treat the transcriptomes monolithically, implicitly ignoring that each gene is likely to have a specific pattern of transcriptional variation across organs and species.

Results: We use linear models to quantify this pattern. We find a continuum in the spectrum of expression variation: the expression of some genes varies considerably across species and little across organs, and simply reflects evolutionary distance. At the other extreme are genes whose expression varies considerably across organs and little across species; these genes are much more likely to be associated with diseases than are genes whose expression varies predominantly across species.

Conclusions: Whether transcriptomes, when considered globally, cluster preferentially according to one component or the other may not be a property of the transcriptomes, but rather a consequence of the dominant behavior of a subset of genes. Therefore, the values of the components of the variance of expression for each gene could become a useful resource when planning, interpreting, and extrapolating experimental data from mouse to humans.
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http://dx.doi.org/10.1186/s13059-016-1008-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937605PMC
July 2016

Enhanced transcriptome maps from multiple mouse tissues reveal evolutionary constraint in gene expression.

Nat Commun 2015 Jan 13;6:5903. Epub 2015 Jan 13.

Functional Genomics Group, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.

Mice have been a long-standing model for human biology and disease. Here we characterize, by RNA sequencing, the transcriptional profiles of a large and heterogeneous collection of mouse tissues, augmenting the mouse transcriptome with thousands of novel transcript candidates. Comparison with transcriptome profiles in human cell lines reveals substantial conservation of transcriptional programmes, and uncovers a distinct class of genes with levels of expression that have been constrained early in vertebrate evolution. This core set of genes captures a substantial fraction of the transcriptional output of mammalian cells, and participates in basic functional and structural housekeeping processes common to all cell types. Perturbation of these constrained genes is associated with significant phenotypes including embryonic lethality and cancer. Evolutionary constraint in gene expression levels is not reflected in the conservation of the genomic sequences, but is associated with conserved epigenetic marking, as well as with characteristic post-transcriptional regulatory programme, in which sub-cellular localization and alternative splicing play comparatively large roles.
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http://dx.doi.org/10.1038/ncomms6903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4308717PMC
January 2015

A comparative encyclopedia of DNA elements in the mouse genome.

Nature 2014 Nov;515(7527):355-64

Bioinformatics and Genomics, Centre for Genomic Regulation (CRG) and UPF, Doctor Aiguader, 88, 08003 Barcelona, Catalonia, Spain.

The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization. Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases.
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http://dx.doi.org/10.1038/nature13992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266106PMC
November 2014

Comparative analysis of the transcriptome across distant species.

Nature 2014 Aug;512(7515):445-8

Functional Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.

The transcriptome is the readout of the genome. Identifying common features in it across distant species can reveal fundamental principles. To this end, the ENCODE and modENCODE consortia have generated large amounts of matched RNA-sequencing data for human, worm and fly. Uniform processing and comprehensive annotation of these data allow comparison across metazoan phyla, extending beyond earlier within-phylum transcriptome comparisons and revealing ancient, conserved features. Specifically, we discover co-expression modules shared across animals, many of which are enriched in developmental genes. Moreover, we use expression patterns to align the stages in worm and fly development and find a novel pairing between worm embryo and fly pupae, in addition to the embryo-to-embryo and larvae-to-larvae pairings. Furthermore, we find that the extent of non-canonical, non-coding transcription is similar in each organism, per base pair. Finally, we find in all three organisms that the gene-expression levels, both coding and non-coding, can be quantitatively predicted from chromatin features at the promoter using a 'universal model' based on a single set of organism-independent parameters.
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http://dx.doi.org/10.1038/nature13424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4155737PMC
August 2014

Landscape of transcription in human cells.

Nature 2012 Sep;489(7414):101-8

Centre for Genomic Regulation and UPF, Doctor Aiguader 88, Barcelona 08003, Catalonia, Spain.

Eukaryotic cells make many types of primary and processed RNAs that are found either in specific subcellular compartments or throughout the cells. A complete catalogue of these RNAs is not yet available and their characteristic subcellular localizations are also poorly understood. Because RNA represents the direct output of the genetic information encoded by genomes and a significant proportion of a cell's regulatory capabilities are focused on its synthesis, processing, transport, modification and translation, the generation of such a catalogue is crucial for understanding genome function. Here we report evidence that three-quarters of the human genome is capable of being transcribed, as well as observations about the range and levels of expression, localization, processing fates, regulatory regions and modifications of almost all currently annotated and thousands of previously unannotated RNAs. These observations, taken together, prompt a redefinition of the concept of a gene.
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http://dx.doi.org/10.1038/nature11233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684276PMC
September 2012

An encyclopedia of mouse DNA elements (Mouse ENCODE).

Genome Biol 2012 Aug 13;13(8):418. Epub 2012 Aug 13.

To complement the human Encyclopedia of DNA Elements (ENCODE) project and to enable a broad range of mouse genomics efforts, the Mouse ENCODE Consortium is applying the same experimental pipelines developed for human ENCODE to annotate the mouse genome.
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http://dx.doi.org/10.1186/gb-2012-13-8-418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491367PMC
August 2012

Evidence for transcript networks composed of chimeric RNAs in human cells.

PLoS One 2012 4;7(1):e28213. Epub 2012 Jan 4.

Bioinformatics and Genomics, Centre for Genomic Regulation and Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.

The classic organization of a gene structure has followed the Jacob and Monod bacterial gene model proposed more than 50 years ago. Since then, empirical determinations of the complexity of the transcriptomes found in yeast to human has blurred the definition and physical boundaries of genes. Using multiple analysis approaches we have characterized individual gene boundaries mapping on human chromosomes 21 and 22. Analyses of the locations of the 5' and 3' transcriptional termini of 492 protein coding genes revealed that for 85% of these genes the boundaries extend beyond the current annotated termini, most often connecting with exons of transcripts from other well annotated genes. The biological and evolutionary importance of these chimeric transcripts is underscored by (1) the non-random interconnections of genes involved, (2) the greater phylogenetic depth of the genes involved in many chimeric interactions, (3) the coordination of the expression of connected genes and (4) the close in vivo and three dimensional proximity of the genomic regions being transcribed and contributing to parts of the chimeric RNAs. The non-random nature of the connection of the genes involved suggest that chimeric transcripts should not be studied in isolation, but together, as an RNA network.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0028213PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3251577PMC
May 2012

The developmental transcriptome of Drosophila melanogaster.

Nature 2011 Mar 22;471(7339):473-9. Epub 2010 Dec 22.

Department of Genetics and Developmental Biology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, Connecticut 06030-6403, USA.

Drosophila melanogaster is one of the most well studied genetic model organisms; nonetheless, its genome still contains unannotated coding and non-coding genes, transcripts, exons and RNA editing sites. Full discovery and annotation are pre-requisites for understanding how the regulation of transcription, splicing and RNA editing directs the development of this complex organism. Here we used RNA-Seq, tiling microarrays and cDNA sequencing to explore the transcriptome in 30 distinct developmental stages. We identified 111,195 new elements, including thousands of genes, coding and non-coding transcripts, exons, splicing and editing events, and inferred protein isoforms that previously eluded discovery using established experimental, prediction and conservation-based approaches. These data substantially expand the number of known transcribed elements in the Drosophila genome and provide a high-resolution view of transcriptome dynamics throughout development.
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http://dx.doi.org/10.1038/nature09715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3075879PMC
March 2011
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