Biomedical subjects

Jill P Mesirov

Publications and source records attributed to Jill P Mesirov.

17 recordsLinked to original sources

PubMed2026

Local delivery of interferon restores antigen presentation and sensitizes medulloblastoma to T cell killing.

Medulloblastomas are considered immunologically cold and refractory to immunotherapy. One factor contributing to their low immunogenicity is impaired antigen presentation, which allows tumor cells to evade cytotoxic T cells. Using a syngeneic mouse model of medulloblastoma, we demonstrate that despite low expression of MHC class I on tumor cells, depletion of CD8+ T cells accelerates tumor growth, whereas adoptive transfer of tumor-reactive CD8+ T cells prolongs survival. These antitumor effects rely on T cell-derived interferon gamma (IFNγ), which induces MHC class I on tumor cells and facilitates tumor cell killing by T cells. Importantly, delivering IFNγ directly into tumors via convection-enhanced delivery enhances CD8+ T cell-mediated killing of tumor cells and significantly prolongs survival in tumor-bearing mice. These studies highlight the importance of T cells in controlling brain tumors and the value of IFNγ as an adjuvant for T cell-based immunotherapy.

Animals↗

PubMed2026

igv-reports: embedding interactive genomic visualizations in HTML reports to aid variant review.

SUMMARY: We present igv-reports, a command-line tool to create standalone HTML pages embedding interactive genomic visualizations of read alignments and associated annotations to support variant inspection workflows. The reports contain all data and code required for visualization of the variant sites, with no dependencies on the input data files. AVAILABILITY AND IMPLEMENTATION: igv-reports is a command-line application written in Python. It is freely available at https://github.com/igvteam/igv-reports under an MIT license.

Software↗

PubMed2023

3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma.

Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment. Although molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis in primary and relapsed ependymoma tumors, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression. In particular, we observe the formation of new topologically associating domains ('neo-TADs') caused by structural variants, group-specific 3D chromatin loops, and the replacement of CTCF insulators by DNA hyper-methylation. Through inhibition experiments, we validate that genes implicated by these 3D genome conformations are essential for the survival of patient-derived ependymoma models in a group-specific manner. Thus, this study extends our ability to reveal tumor-dependency genes by 3D genome conformations even in tumors that lack targetable genetic alterations.

Child↗

PubMed2006

Combo: a whole genome comparative browser.

SUMMARY: Combo is a comparative genome browser that provides a dynamic view of whole genome alignments along with their associated annotations. Combo provides two different visualization perspectives. The perpendicular (dot plot) view provides a dot plot of genome alignments synchronized with a display of genome annotations along each axis. The parallel view displays two genome annotations horizontally, synchronized through a panel displaying local alignments as trapezoids. Users can zoom to any resolution, from whole chromosomes to individual bases. They can select, highlight and view detailed information from specific alignments and annotations. Combo is an organism agnostic and can import data from a variety of file formats. AVAILABILITY: Combo is integrated as part of the Argo Genome Browser which also provides single-genome browsing and editing capabilities. Argo is written in Java, runs on multiple platforms and is freely available for download at http://www.broad.mit.edu/annotation/argo/.

Algorithms↗

PubMed2006

Comparative gene marker selection suite.

MOTIVATION: An important step in analyzing expression profiles from microarray data is to identify genes that can discriminate between distinct classes of samples. Many statistical approaches for assigning significance values to genes have been developed. The Comparative Marker Selection suite consists of three modules that allow users to apply and compare different methods of computing significance for each marker gene, a viewer to assess the results, and a tool to create derivative datasets and marker lists based on user-defined significance criteria. AVAILABILITY: The Comparative Marker Selection application suite is freely available as a GenePattern module. The GenePattern analysis environment is freely available at http://www.broad.mit.edu/genepattern.

Algorithms↗

PubMed2006

GenePattern 2.0.

Explore the source record for details and available documents.

Gene Expression Profiling↗

PubMed2005

Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation.

Snf5 (Ini1/Baf47/Smarcb1), a core member of the Swi/Snf chromatin remodeling complex, is a potent tumor suppressor whose mechanism of action is largely unknown. Biallelic loss of Snf5 leads to the onset of aggressive cancers in both humans and mice. We have developed an innovative and widely applicable analytical technique for cross-species validation of cancer models and show that the gene expression profiles of our Snf5 murine models closely resemble those of human Snf5-deficient rhabdoid tumors. We exploit this system to produce what we believe to be the first report documenting the effects on gene expression of inactivating a Swi/Snf subunit in normal mammalian cells and to identify the transcriptional pathways regulated by Snf5. We demonstrate that the tumor suppressor activity of Snf5 depends on its regulation of cell cycle progression; Snf5 inactivation leads to aberrant up-regulation of E2F targets and increased levels of p53 that are accompanied by apoptosis, polyploidy, and growth arrest. Further, conditional mouse models demonstrate that inactivation of p16Ink4a or Rb (retinoblastoma) does not accelerate tumor formation in Snf5 conditional mice, whereas mutation of p53 leads to a dramatic acceleration of tumor formation.

Animals↗

PubMed2005

Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.

Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.

Cell Line, Tumor↗

PubMed2005

GeneCruiser: a web service for the annotation of microarray data.

SUMMARY: GeneCruiser is a web service allowing users to annotate their genomic data by mapping microarray feature identifiers to gene identifiers from databases, such as UniGene, while providing links to web resources, such as the UCSC Genome Browser. It relies on a regularly updated database that retrieves and indexes the mappings between microarray probes and genomic databases. Genes are identified using the Life Sciences Identifier standard. AVAILABILITY: GeneCruiser is freely available in the following forms: Web service and Web application, http://www.genecruiser.org; GenePattern, GeneCruiser access has been integrated into our microarray analysis platform, GenePattern. http://www.genepattern.org.

Animals↗

PubMed2005

Assembly of polymorphic genomes: algorithms and application to Ciona savignyi.

Whole-genome assembly is now used routinely to obtain high-quality draft sequence for the genomes of species with low levels of polymorphism. However, genome assembly remains extremely challenging for highly polymorphic species. The difficulty arises because two divergent haplotypes are sequenced together, making it difficult to distinguish alleles at the same locus from paralogs at different loci. We present here a method for assembling highly polymorphic diploid genomes that involves assembling the two haplotypes separately and then merging them to obtain a reference sequence. Our method was developed to assemble the genome of the sea squirt Ciona savignyi, which was sequenced to a depth of 12.7 x from a single wild individual. By comparing finished clones of the two haplotypes we determined that the sequenced individual had an extremely high heterozygosity rate, averaging 4.6% with significant regional variation and rearrangements at all physical scales. Applied to these data, our method produced a reference assembly covering 157 Mb, with N50 contig and scaffold sizes of 47 kb and 989 kb, respectively. Alignment of ESTs indicates that 88% of loci are present at least once and 81% exactly once in the reference assembly. Our method represented loci in a single copy more reliably and achieved greater contiguity than a conventional whole-genome assembly method.

Algorithms↗

PubMed2004

Improving genome annotations using phylogenetic profile anomaly detection.

MOTIVATION: A promising strategy for refining genome annotations is to detect features that conflict with known functional or evolutionary relationships between groups of genes. Previous work in this area has been focused on investigating the absence of 'housekeeping' genes or components of well-studied pathways. We have sought to develop a method for improving new annotations that can automatically synthesize and use the information available in a database of other annotated genomes. RESULTS: We show that a probabilistic model of phylogenetic profiles, trained from a database of curated genome annotations, can be used to reliably detect errors in new annotations. We use our method to identify 22 genes that were missed in previously published annotations of prokaryotic genomes. AVAILABILITY: The method was evaluated using MATLAB and open source software referenced in this work. Scripts and datasets are available from the authors upon request. CONTACT: tarjei@broad.mit.edu.

Algorithms↗

PubMed2004

Metagenes and molecular pattern discovery using matrix factorization.

We describe here the use of nonnegative matrix factorization (NMF), an algorithm based on decomposition by parts that can reduce the dimension of expression data from thousands of genes to a handful of metagenes. Coupled with a model selection mechanism, adapted to work for any stochastic clustering algorithm, NMF is an efficient method for identification of distinct molecular patterns and provides a powerful method for class discovery. We demonstrate the ability of NMF to recover meaningful biological information from cancer-related microarray data. NMF appears to have advantages over other methods such as hierarchical clustering or self-organizing maps. We found it less sensitive to a priori selection of genes or initial conditions and able to detect alternative or context-dependent patterns of gene expression in complex biological systems. This ability, similar to semantic polysemy in text, provides a general method for robust molecular pattern discovery.

Algorithms↗

PubMed2003

PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes.

DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1alpha and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.

Animals↗

PubMed2003

Estimating dataset size requirements for classifying DNA microarray data.

A statistical methodology for estimating dataset size requirements for classifying microarray data using learning curves is introduced. The goal is to use existing classification results to estimate dataset size requirements for future classification experiments and to evaluate the gain in accuracy and significance of classifiers built with additional data. The method is based on fitting inverse power-law models to construct empirical learning curves. It also includes a permutation test procedure to assess the statistical significance of classification performance for a given dataset size. This procedure is applied to several molecular classification problems representing a broad spectrum of levels of complexity.

Algorithms↗

PubMed2003

Whole-genome sequence assembly for mammalian genomes: Arachne 2.

We previously described the whole-genome assembly program Arachne, presenting assemblies of simulated data for small to mid-sized genomes. Here we describe algorithmic adaptations to the program, allowing for assembly of mammalian-size genomes, and also improving the assembly of smaller genomes. Three principal changes were simultaneously made and applied to the assembly of the mouse genome, during a six-month period of development: (1) Supercontigs (scaffolds) were iteratively broken and rejoined using several criteria, yielding a 64-fold increase in length (N50), and apparent elimination of all global misjoins; (2) gaps between contigs in supercontigs were filled (partially or completely) by insertion of reads, as suggested by pairing within the supercontig, increasing the N50 contig length by 50%; (3) memory usage was reduced fourfold. The outcome of this mouse assembly and its analysis are described in (Mouse Genome Sequencing Consortium 2002).

Animals↗

PubMed2002

Prediction of central nervous system embryonal tumour outcome based on gene expression.

Embryonal tumours of the central nervous system (CNS) represent a heterogeneous group of tumours about which little is known biologically, and whose diagnosis, on the basis of morphologic appearance alone, is controversial. Medulloblastomas, for example, are the most common malignant brain tumour of childhood, but their pathogenesis is unknown, their relationship to other embryonal CNS tumours is debated, and patients' response to therapy is difficult to predict. We approached these problems by developing a classification system based on DNA microarray gene expression data derived from 99 patient samples. Here we demonstrate that medulloblastomas are molecularly distinct from other brain tumours including primitive neuroectodermal tumours (PNETs), atypical teratoid/rhabdoid tumours (AT/RTs) and malignant gliomas. Previously unrecognized evidence supporting the derivation of medulloblastomas from cerebellar granule cells through activation of the Sonic Hedgehog (SHH) pathway was also revealed. We show further that the clinical outcome of children with medulloblastomas is highly predictable on the basis of the gene expression profiles of their tumours at diagnosis.

Adolescent↗

PubMed2002

ARACHNE: a whole-genome shotgun assembler.

We describe a new computer system, called ARACHNE, for assembling genome sequence using paired-end whole-genome shotgun reads. ARACHNE has several key features, including an efficient and sensitive procedure for finding read overlaps, a procedure for scoring overlaps that achieves high accuracy by correcting errors before assembly, read merger based on forward-reverse links, and detection of repeat contigs by forward-reverse link inconsistency. To test ARACHNE, we created simulated reads providing approximately 10-fold coverage of the genomes of H. influenzae, S. cerevisiae, and D. melanogaster, as well as human chromosomes 21 and 22. The assemblies of these simulated reads yielded nearly complete coverage of the respective genomes, with a small number of contigs joined into a smaller number of supercontigs (or scaffolds). For example, analysis of the D. melanogaster genome yielded approximately 98% coverage with an N50 contig length of 324 kb and an N50 supercontig length of 5143 kb. The assembly accuracy was high, although not perfect: small errors occurred at a frequency of roughly 1 per 1 Mb (typically, deletion of approximately 1 kb in size), with a very small number of other misassemblies. The assembly was rapid: the Drosophila assembly required only 21 hours on a single 667 MHz processor and used 8.4 Gb of memory.

Algorithms↗