Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer.
Journal of Hepatology 65(2):325 (2016)
Pediatric liver cancer is a rare but serious disease whose incidence is rising, and for which the therapeutic options are limited. Development of more targeted, less toxic therapies is hindered by the lack of an experimental animal model that captures the heterogeneity and metastatic capability ...
Cupid: simultaneous reconstruction of microRNA-target and ceRNA networks.
Genome Research 25(2):257 (2015)
We introduce a method for simultaneous prediction of microRNA-target interactions and their mediated competitive endogenous RNA (ceRNA) interactions. Using high-throughput validation assays in breast cancer cell lines, we show that our integrative approach significantly improves on microRNA-targ...
Interrogation of a context-specific transcription factor network identifies novel regulators of pluripotency.
Stem Cells 33(2):367 (2015)
The predominant view of pluripotency regulation proposes a stable ground state with coordinated expression of key transcription factors (TFs) that prohibit differentiation. Another perspective suggests a more complexly regulated state involving competition between multiple lineage-specifying TFs...
Recurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney.
Nature Communications 6:8891 (2015)
The X-linked BCL-6 co-repressor (BCOR) gene encodes a key constituent of a variant polycomb repressive complex (PRC) that is mutated or translocated in human cancers. Here we report on the identification of somatic internal tandem duplications (ITDs) clustering in the C terminus of BCOR in 23 of...
Direct ChIP-Seq significance analysis improves target prediction.
BMC Genomics 16 Suppl 5:S4 (2015)
Chromatin immunoprecipitation followed by sequencing of protein-bound DNA fragments (ChIP-Seq) is an effective high-throughput methodology for the identification of context specific DNA fragments that are bound by specific proteins in vivo. Despite significant progress in the bioinformatics anal...
Overexpression and constitutive nuclear localization of cohesin protease Separase protein correlates with high incidence of relapse and reduced overall survival in glioblastoma multiforme.
Journal of Neuro-Oncology 119(1):27 (2014)
Separase, an enzyme that cleaves the chromosomal cohesin during mitosis, is overexpressed in a wide range of human epithelial cancers of breast, bone and prostate (Meyer et al., Clin Cancer Res 15(8):2703-2710, 2009). Overexpression of Separase in animal models results in aneuploidy and tumorige...
The miR-424(322)/503 cluster orchestrates remodeling of the epithelium in the involuting mammary gland.
Genes & Development 28(7):765 (2014)
The mammary gland is a very dynamic organ that undergoes continuous remodeling. The critical regulators of this process are not fully understood. Here we identify the microRNA cluster miR-424(322)/503 as an important regulator of epithelial involution after pregnancy. Through the generation of a...
A molecular signature predictive of indolent prostate cancer.
Science Translational Medicine 5(202):202ra122 (2013)
Many newly diagnosed prostate cancers present as low Gleason score tumors that require no treatment intervention. Distinguishing the many indolent tumors from the minority of lethal ones remains a major clinical challenge. We now show that low Gleason score prostate tumors can be distinguished a...
tRNA-derived microRNA modulates proliferation and the DNA damage response and is down-regulated in B cell lymphoma.
PNAS 110(4):1404 (2013)
Sequencing studies from several model systems have suggested that diverse and abundant small RNAs may be derived from tRNA, but the function of these molecules remains undefined. Here, we demonstrate that one such tRNA-derived fragment, cloned from human mature B cells and designated CU1276, in ...
Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension.
Circulation: Cardiovascular Genetics 5(3):336 (2012)
Heritable and idiopathic pulmonary arterial hypertension (PAH) are phenotypically identical and associated with mutations in several genes related to transforming growth factor (TGF) beta signaling, including bone morphogenetic protein receptor type 2, activin receptor-like kinase 1, endoglin, a...
An extensive microRNA-mediated network of RNA-RNA interactions regulates established oncogenic pathways in glioblastoma.
Cell 147(2):370 (2011)
By analyzing gene expression data in glioblastoma in combination with matched microRNA profiles, we have uncovered a posttranscriptional regulation layer of surprising magnitude, comprising more than 248,000 microRNA (miR)-mediated interactions. These include ∼7,000 genes whose transcripts act a...
A human B-cell interactome identifies MYB and FOXM1 as master regulators of proliferation in germinal centers.
Molecular Systems Biology 6:377 (2010)
Assembly of a transcriptional and post-translational molecular interaction network in B cells, the human B-cell interactome (HBCI), reveals a hierarchical, transcriptional control module, where MYB and FOXM1 act as synergistic master regulators of proliferation in the germinal center (GC). Eight...
Integrated biochemical and computational approach identifies BCL6 direct target genes controlling multiple pathways in normal germinal center B cells.
Blood 115(5):975 (2010)
BCL6 is a transcriptional repressor required for mature B-cell germinal center (GC) formation and implicated in lymphomagenesis. BCL6's physiologic function is only partially known because the complete set of its targets in GC B cells has not been identified. To address this issue, we used an in...
A systems biology approach to transcription factor binding site prediction.
PLoS ONE 5(3):e9878 (2010)
The elucidation of mammalian transcriptional regulatory networks holds great promise for both basic and translational research and remains one the greatest challenges to systems biology. Recent reverse engineering methods deduce regulatory interactions from large-scale mRNA expression profiles a...
BCL6 suppression of BCL2 via Miz1 and its disruption in diffuse large B cell lymphoma.
PNAS 106(27):11294 (2009)
The BCL6 proto-oncogene encodes a transcriptional repressor that is required for germinal center (GC) formation and whose deregulation by genomic lesions is implicated in the pathogenesis of GC-derived diffuse large B cell lymphoma (DLBCL) and, less frequently, follicular lymphoma (FL). The biol...
Identification of the human mature B cell miRNome.
Immunity 30(5):744 (2009)
The full set of microRNAs (miRNAs) in the human genome is not known. Because presently known miRNAs have been identified by virtue of their abundant expression in a few cell types, many tissue-specific miRNAs remain unrevealed. To understand the role of miRNAs in B cell function and lymphomagene...
ChIP-on-chip significance analysis reveals large-scale binding and regulation by human transcription factor oncogenes.
PNAS 106(1):244 (2009)
ChIP-on-chip has emerged as a powerful tool to dissect the complex network of regulatory interactions between transcription factors and their targets. However, most ChIP-on-chip analysis methods use conservative approaches aimed at minimizing false-positive transcription factor targets. We prese...
Correlating measurements across samples improves accuracy of large-scale expression profile experiments.
Genome Biology 10(12):R143 (2009)
Gene expression profiling technologies suffer from poor reproducibility across replicate experiments. However, when analyzing large datasets, probe-level expression profile correlation can help identify flawed probes and lead to the construction of truer probe sets with improved reproducibility....
Tissue-specific regulatory elements in mammalian promoters.
Molecular Systems Biology 3:73 (2007)
Transcription factor-binding sites and the cis-regulatory modules they compose are central determinants of gene expression. We previously showed that binding site motifs and modules in proximal promoters can be used to predict a significant portion of mammalian tissue-specific transcription. Her...
DNA motifs in human and mouse proximal promoters predict tissue-specific expression.
PNAS 103(16):6275 (2006)
Comprehensive identification of cis-regulatory elements is necessary for accurately reconstructing gene regulatory networks. We studied proximal promoters of human and mouse genes with differential expression across 56 terminally differentiated tissues. Using in silico techniques to discover, ev...