X Shirley Liu

Dana-Farber Cancer Institute, Boston, Massachusetts, United States

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Publications (129)1697.63 Total impact

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    Peng Jiang, X Shirley Liu
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    ABSTRACT: Recent years have seen the rapid growth of large-scale biological data, but the effective mining and modeling of 'big data' for new biological discoveries remains a significant challenge. A new study reanalyzes expression profiles from the Gene Expression Omnibus to make novel discoveries about genes involved in DNA damage repair and genome instability in cancer.
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    ABSTRACT: We propose the Model-based Analysis of Genome-wide CRISPR/Cas9 Knockout (MAGeCK) method for prioritizing single-guide RNAs, genes and pathways in genome-scale CRISPR/Cas9 knockout screens. MAGeCK demonstrates better performance compared with existing methods, identifies both positively and negatively selected genes simultaneously, and reports robust results across different experimental conditions. Using public datasets, MAGeCK identified novel essential genes and pathways, including EGFR in vemurafenib-treated A375 cells harboring a BRAF mutation. MAGeCK also detected cell type-specific essential genes, including BCR and ABL1, in KBM7 cells bearing a BCR-ABL fusion, and IGF1R in HL-60 cells, which depends on the insulin signaling pathway for proliferation. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0554-4) contains supplementary material, which is available to authorized users.
    Genome Biology 12/2014; 15(12):554. DOI:10.1186/PREACCEPT-1316450832143458 · 10.47 Impact Factor
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    ABSTRACT: Graphical Abstract Highlights d LSD1 is broadly associated with AR-regulated enhancers, and a subset is H3T6ph marked d LSD1 is associated with CoREST at these sites and interacts with FOXA1 d Despite coactivator function at these sites, LSD1 mediates their H3K4 demethylation d LSD1 coactivation is through demethylation of novel histone or nonhistone substrates In Brief Cai et al. show that lysine-specific demethylase 1 (LSD1), although generally a transcriptional corepressor through H3K4 demethylation, functions broadly as a coactivator for androgen receptor and interacts with FOXA1 on androgen-stimulated genes. LSD1-mediated H3K4 demethylation persists at these sites, indicating a distinct coactivator function mediated by demethylation of other substrates.
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    ABSTRACT: Lysine-Specific Demethylase 1 (LSD1, KDM1A) functions as a transcriptional corepressor through demethylation of histone 3 lysine 4 (H3K4) but has a coactivator function on some genes through mechanisms that are unclear. We show that LSD1, interacting with CoREST, associates with and coactivates androgen receptor (AR) on a large fraction of androgen-stimulated genes. A subset of these AR/LSD1-associated enhancer sites have histone 3 threonine 6 phosphorylation (H3T6ph), and these sites are further enriched for androgen-stimulated genes. Significantly, despite its coactivator activity, LSD1 still mediates H3K4me2 demethylation at these androgen-stimulated enhancers. FOXA1 is also associated with LSD1 at AR-regulated enhancer sites, and a FOXA1 interaction with LSD1 enhances binding of both proteins at these sites. These findings show that LSD1 functions broadly as a regulator of AR function, that it maintains a transcriptional repression function at AR-regulated enhancers through H3K4 demethylation, and that it has a distinct AR-linked coactivator function mediated by demethylation of other substrates. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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    ABSTRACT: Activation-induced cytidine deaminase (AID) initiates both somatic hypermutation (SHM) for antibody affinity maturation and DNA breakage for antibody class switch recombination (CSR) via transcription-dependent cytidine deamination of single-stranded DNA targets. Though largely specific for immunoglobulin genes, AID also acts on a limited set of off-targets, generating oncogenic translocations and mutations that contribute to B cell lymphoma. How AID is recruited to off-targets has been a long-standing mystery. Based on deep GRO-seq studies of mouse and human B lineage cells activated for CSR or SHM, we report that most robust AID off-target translocations occur within highly focal regions of target genes in which sense and antisense transcription converge. Moreover, we found that such AID-targeting "convergent" transcription arises from antisense transcription that emanates from super-enhancers within sense transcribed gene bodies. Our findings provide an explanation for AID off-targeting to a small subset of mostly lineage-specific genes in activated B cells. Copyright © 2014 Elsevier Inc. All rights reserved.
    Cell 12/2014; 159(7). DOI:10.1016/j.cell.2014.11.014 · 33.12 Impact Factor
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    ABSTRACT: Notch signaling has pleiotropic context-specific functions that have essential roles in many processes, including embryonic development and maintenance and homeostasis of adult tissues. Aberrant Notch signaling (both hyper- and hypoactive) is implicated in a number of human developmental disorders and many cancers. Notch receptor signaling is mediated by tightly regulated proteolytic cleavages that lead to the assembly of a nuclear Notch transcription complex, which drives the expression of downstream target genes and thereby executes Notch's functions. Thus, understanding regulation of gene expression by Notch is central to deciphering how Notch carries out its many activities. Here, we summarize the recent findings pertaining to the complex interplay between the Notch transcriptional complex and interacting factors involved in transcriptional regulation, including co-activators, cooperating transcription factors, and chromatin regulators, and discuss emerging data pertaining to the role of Notch-regulated noncoding RNAs in transcription. This article is protected by copyright. All rights reserved
    Journal of Cellular Physiology 11/2014; DOI:10.1002/jcp.24872 · 3.87 Impact Factor
  • Clifford A Meyer, X Shirley Liu
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    ABSTRACT: Next-generation sequencing (NGS) technologies have been used in diverse ways to investigate various aspects of chromatin biology by identifying genomic loci that are bound by transcription factors, occupied by nucleosomes or accessible to nuclease cleavage, or loci that physically interact with remote genomic loci. However, reaching sound biological conclusions from such NGS enrichment profiles requires many potential biases to be taken into account. In this Review, we discuss common ways in which biases may be introduced into NGS chromatin profiling data, approaches to diagnose these biases and analytical techniques to mitigate their effect.
    Nature Reviews Genetics 09/2014; 15(11). DOI:10.1038/nrg3788 · 39.79 Impact Factor
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    ABSTRACT: Tissues may adopt diverse strategies to establish specific transcriptional programs in daughter lineages. In intestinal crypts, enhancers for genes expressed in both major cell types appear broadly permissive in stem and specified progenitor cells. In blood, another self-renewing tissue, it is unclear when chromatin becomes permissive for transcription of genes expressed in distinct terminal lineages. Using chromatin immunoprecipitation (ChIP) combined with deep sequencing (ChIP-seq) to profile activating histone marks, we studied enhancer dynamics in primary mouse blood stem, progenitor, and specified cells. Stem and multipotent progenitor cells show scant H3K4me2 marking at enhancers bound by specific transcription factors in their committed progeny. Rather, enhancers are modulated dynamically and serially, with substantial loss and gain of H3K4me2, at each cellular transition. Quantitative analysis of these dynamics accurately modeled hematopoiesis according to Waddington's notion of epigenotypes. Delineation of enhancers in terminal blood lineages coincides with cell specification, and enhancers active in single lineages show well-positioned H3K4me2- and H3K27ac-marked nucleosomes and DNaseI hypersensitivity in other cell types, revealing limited lineage fidelity. These findings demonstrate that enhancer chronology in blood cells differs markedly from that in intestinal crypts. Chromatin dynamics in hematopoiesis provide a useful foundation to consider classical observations such as cellular reprogramming and multilineage locus priming.
    Genes & Development 08/2014; 28(16):1827-39. DOI:10.1101/gad.240101.114 · 12.64 Impact Factor
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    ABSTRACT: Next generation sequencing was used to identify Notch mutations in a large collection of diverse solid tumors. NOTCH1 and NOTCH2 rearrangements leading to constitutive receptor activation were confined to triple negative breast cancers (TNBC, 6 of 66 tumors). TNBC cell lines with NOTCH1 rearrangements associated with high levels of activated NOTCH1 (N1-ICD) were sensitive to the gamma-secretase inhibitor (GSI) MRK-003, both alone and in combination with pacitaxel, in vitro and in vivo, whereas cell lines with NOTCH2 rearrangements were resistant to GSI. Immunohistochemical staining of N1-ICD in TNBC xenografts correlated with responsiveness, and expression levels of the direct Notch target gene HES4 correlated with outcome in TNBC patients. Activating NOTCH1 point mutations were also identified in other solid tumors, including adenoid cystic carcinoma (ACC). Notably, ACC primary tumor xenografts with activating NOTCH1 mutations and high N1-ICD levels were sensitive to GSI, whereas N1-ICD-low tumors without NOTCH1 mutations were resistant. Significance: NOTCH1 mutations, immunohistochemical staining for activated NOTCH1, and HES4 expression are biomarkers that can be used to identify solid tumors that are likely to respond to gamma-secretase inhibitor-based therapies.
    Cancer Discovery 08/2014; DOI:10.1158/2159-8290.CD-13-0830 · 15.93 Impact Factor
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    ABSTRACT: Recurrent mutations in histone-modifying enzymes imply key roles in tumorigenesis, yet their functional relevance is largely unknown. Here, we show that JARID1B, encoding a histone H3 lysine 4 (H3K4) demethylase, is frequently amplified and overexpressed in luminal breast tumors and a somatic mutation in a basal-like breast cancer results in the gain of unique chromatin binding and luminal expression and splicing patterns. Downregulation of JARID1B in luminal cells induces basal genes expression and growth arrest, which is rescued by TGFβ pathway inhibitors. Integrated JARID1B chromatin binding, H3K4 methylation, and expression profiles suggest a key function for JARID1B in luminal cell-specific expression programs. High luminal JARID1B activity is associated with poor outcome in patients with hormone receptor-positive breast tumors.
    Cancer Cell 06/2014; 25(6):762-777. DOI:10.1016/j.ccr.2014.04.024 · 23.89 Impact Factor
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    ABSTRACT: Chromatin regulators play an important role in the development of human diseases. In this study, we focused on Plant Homeo Domain Finger protein 8 (PHF8), a chromatin regulator that has attracted special concern recently. PHF8 is a histone lysine demethylase ubiquitously expressed in nuclei. Mutations of PHF8 are associated with X-linked mental retardation. It usually functions as a transcriptional co-activator by associating with H3K4me3 and RNA polymerase II. We found that PHF8 may associate with another regulator, REST/NRSF, predominately at promoter regions via studying several published PHF8 chromatin immunoprecipitation-sequencing (ChIP-Seq) datasets. Our analysis suggested that PHF8 not only activates but may also repress gene expression.
    Scientific Reports 05/2014; 4:5008. DOI:10.1038/srep05008 · 5.08 Impact Factor
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    ABSTRACT: Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer's disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer's disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid β-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling. However, in Alzheimer's disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.
    Nature 03/2014; 507(7493):448-54. DOI:10.1038/nature13163 · 42.35 Impact Factor
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    ABSTRACT: Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization1. One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE12 and its substrate XBP13. Previous studies report UPR activation in various human tumors4-6, but XBP1's role in cancer progression in mammary epithelial cells is largely unknown. Triple negative breast cancer (TNBC), a form of breast cancer in which tumor cells do not express the genes for estrogen receptor, progesterone receptor, and Her2/neu, is a highly aggressive malignancy with limited treatment options7, 8. Here, we report that XBP1 is activated in TNBC and plays a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumor growth and tumor relapse and reduced the CD44high/CD24low population. Hypoxia-inducing factor (HIF)1α is known to be hyperactivated in TNBCs 9, 10. Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that regulates the expression of HIF1α targets via the recruitment of RNA polymerase II. Analysis of independent cohorts of patients with TNBC revealed a specific XBP1 gene expression signature that was highly correlated with HIF1α and hypoxia-driven signatures and that strongly associated with poor prognosis. Our findings reveal a key function for the XBP1 branch of the UPR in TNBC and imply that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.
    Nature 03/2014; 508(7494). DOI:10.1038/nature13119 · 42.35 Impact Factor
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    ABSTRACT: The transcription factor SOX2 is an essential regulator of pluripotent stem cells and promotes development and maintenance of squamous epithelia. We previously reported that SOX2 is an oncogene and subject to highly recurrent genomic amplification in squamous cell carcinomas (SCCs). Here, we have further characterized the function of SOX2 in SCC. Using ChIP-seq analysis, we compared SOX2-regulated gene profiles in multiple SCC cell lines to ES cell profiles and determined that SOX2 binds to distinct genomic loci in SCCs. In SCCs, SOX2 preferentially interacts with the transcription factor p63, as opposed to the transcription factor OCT4, which is the preferred SOX2 binding partner in ES cells. SOX2 and p63 exhibited overlapping genomic occupancy at a large number of loci in SCCs; however, coordinate binding of SOX2 and p63 was absent in ES cells. We further demonstrated that SOX2 and p63 jointly regulate gene expression, including the oncogene ETV4, which was essential for SOX2-amplified SCC cell survival. Together, these findings demonstrate that the action of SOX2 in SCC differs substantially from its role in pluripotency. The identification of the SCC-associated interaction between SOX2 and p63 will enable deeper characterization the downstream targets of this interaction in SCC and normal squamous epithelial physiology.
    The Journal of clinical investigation 03/2014; DOI:10.1172/JCI71545 · 13.77 Impact Factor
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    ABSTRACT: The main oncogenic driver in T-lymphoblastic leukemia is NOTCH1, which activates genes by forming chromatin-associated Notch transcription complexes. Gamma-secretase-inhibitor treatment prevents NOTCH1 nuclear localization, but most genes with NOTCH1-binding sites are insensitive to gamma-secretase inhibitors. Here, we demonstrate that fewer than 10% of NOTCH1-binding sites show dynamic changes in NOTCH1 occupancy when T-lymphoblastic leukemia cells are toggled between the Notch-on and -off states with gamma-secretase inhibiters. Dynamic NOTCH1 sites are functional, being highly associated with Notch target genes, are located mainly in distal enhancers, and frequently overlap with RUNX1 binding. In line with the latter association, we show that expression of IL7R, a gene with key roles in normal T-cell development and in T-lymphoblastic leukemia, is coordinately regulated by Runx factors and dynamic NOTCH1 binding to distal enhancers. Like IL7R, most Notch target genes and associated dynamic NOTCH1-binding sites cooccupy chromatin domains defined by constitutive binding of CCCTC binding factor, which appears to restrict the regulatory potential of dynamic NOTCH1 sites. More remarkably, the majority of dynamic NOTCH1 sites lie in superenhancers, distal elements with exceptionally broad and high levels of H3K27ac. Changes in Notch occupancy produces dynamic alterations in H3K27ac levels across the entire breadth of superenhancers and in the promoters of Notch target genes. These findings link regulation of superenhancer function to NOTCH1, a master regulatory factor and potent oncoprotein in the context of immature T cells, and delineate a generally applicable roadmap for identifying functional Notch sites in cellular genomes.
    Proceedings of the National Academy of Sciences 12/2013; 111(2). DOI:10.1073/pnas.1315023111 · 9.81 Impact Factor
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    ABSTRACT: Sequencing of DNase I hypersensitive sites (DNase-seq) is a powerful technique for identifying cis-regulatory elements across the genome. We studied the key experimental parameters to optimize performance of DNase-seq. Sequencing short fragments of 50-100 base pairs (bp) that accumulate in long internucleosome linker regions was more efficient for identifying transcription factor binding sites compared to sequencing longer fragments. We also assessed the potential of DNase-seq to predict transcription factor occupancy via generation of nucleotide-resolution transcription factor footprints. In modeling the sequence-specific DNase I cutting bias, we found a strong effect that varied over more than two orders of magnitude. This indicates that the nucleotide-resolution cleavage patterns at many transcription factor binding sites are derived from intrinsic DNase I cleavage bias rather than from specific protein-DNA interactions. In contrast, quantitative comparison of DNase I hypersensitivity between states can predict transcription factor occupancy associated with particular biological perturbations.
    Nature Methods 12/2013; DOI:10.1038/nmeth.2762 · 25.95 Impact Factor
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    ABSTRACT: Transcription factor activity and turnover are functionally linked, but the global patterns by which DNA-bound regulators are eliminated remain poorly understood. We established an assay to define the chromosomal location of DNA-associated proteins that are slated for degradation by the ubiquitin-proteasome system. The genome-wide map described here ties proteolysis in mammalian cells to active enhancers and to promoters of specific gene families. Nuclear-encoded mitochondrial genes in particular correlate with protein elimination, which positively affects their transcription. We show that the nuclear receptor corepressor NCoR1 is a key target of proteolysis and physically interacts with the transcription factor CREB. Proteasome inhibition stabilizes NCoR1 in a site-specific manner and restrains mitochondrial activity by repressing CREB-sensitive genes. In conclusion, this functional map of nuclear proteolysis links chromatin architecture with local protein stability and identifies proteolytic derepression as highly dynamic in regulating the transcription of genes involved in energy metabolism.
    Cell 12/2013; 155(6):1380-95. DOI:10.1016/j.cell.2013.11.016 · 33.12 Impact Factor
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    ABSTRACT: Canonical Wnt signaling supports the pluripotency of embryonic stem cells (ESCs) but also promotes differentiation of early mammalian cell lineages. To explain these paradoxical observations, we explored the gene regulatory networks at play. Canonical Wnt signaling is intertwined with the pluripotency network comprising Nanog, Oct4, and Sox2 in mouse ESCs. In defined media supporting the derivation and propagation of ESCs, Tcf3 and β-catenin interact with Oct4; Tcf3 binds to Sox motif within Oct-Sox composite motifs that are also bound by Oct4-Sox2 complexes. Further, canonical Wnt signaling up-regulates the activity of the Pou5f1 distal enhancer via the Sox motif in ESCs. When viewed in the context of published studies on Tcf3 and β-catenin mutants, our findings suggest Tcf3 counters pluripotency by competition with Sox2 at these sites, and Tcf3 inhibition is blocked by β-catenin entry into this complex. Wnt pathway stimulation also triggers β-catenin association at regulatory elements with classic Lef/Tcf motifs associated with differentiation programs. The failure to activate these targets in the presence of a MEK/ERK inhibitor essential for ESC culture suggests MEK/ERK signaling and canonical Wnt signaling combine to promote ESC differentiation.
    Stem Cells 12/2013; 31(12). DOI:10.1002/stem.1371 · 7.70 Impact Factor
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    ABSTRACT: The combination of ChIP-seq and transcriptome analysis is a compelling approach to unravel the regulation of gene expression. Several recently published methods combine transcription factor (TF) binding and gene expression for target prediction, but few of them provide an efficient software package for the community. Binding and expression target analysis (BETA) is a software package that integrates ChIP-seq of TFs or chromatin regulators with differential gene expression data to infer direct target genes. BETA has three functions: (i) to predict whether the factor has activating or repressive function; (ii) to infer the factor's target genes; and (iii) to identify the motif of the factor and its collaborators, which might modulate the factor's activating or repressive function. Here we describe the implementation and features of BETA to demonstrate its application to several data sets. BETA requires ∼1 GB of RAM, and the procedure takes 20 min to complete. BETA is available open source at http://cistrome.org/BETA/.
    Nature Protocol 12/2013; 8(12):2502-2515. DOI:10.1038/nprot.2013.150 · 8.36 Impact Factor
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    ABSTRACT: Diversified histone modifications (HMs) are essential epigenetic features. They play important roles in fundamental biological processes including transcription, DNA repair and DNA replication. Chromatin regulators (CRs), which are indispensable in epigenetics, can mediate HMs to adjust chromatin structures and functions. With the development of ChIP-Seq technology, there is an opportunity to study CR and HM profiles at the whole-genome scale. However, no specific resource for the integration of CR ChIP-Seq data or CR-HM ChIP-Seq linkage pairs is currently available. Therefore, we constructed the CR Cistrome database, available online at http://compbio.tongji.edu.cn/cr and http://cistrome.org/cr/, to further elucidate CR functions and CR-HM linkages. Within this database, we collected all publicly available ChIP-Seq data on CRs in human and mouse and categorized the data into four cohorts: the reader, writer, eraser and remodeler cohorts, together with curated introductions and ChIP-Seq data analysis results. For the HM readers, writers and erasers, we provided further ChIP-Seq analysis data for the targeted HMs and schematized the relationships between them. We believe CR Cistrome is a valuable resource for the epigenetics community.
    Nucleic Acids Research 11/2013; 42(Database issue). DOI:10.1093/nar/gkt1151 · 8.81 Impact Factor

Publication Stats

12k Citations
1,697.63 Total Impact Points

Institutions

  • 2004–2015
    • Dana-Farber Cancer Institute
      • • Department of Biostatistics and Computational Biology
      • • Department of Medical Oncology
      Boston, Massachusetts, United States
  • 2012–2014
    • Tongji University
      Shanghai, Shanghai Shi, China
  • 2005–2014
    • Harvard Medical School
      • • Department of Genetics
      • • Department of Medicine
      Boston, Massachusetts, United States
  • 2003–2014
    • Harvard University
      • Department of Statistics
      Cambridge, Massachusetts, United States
  • 2011
    • Boston Children's Hospital
      Boston, Massachusetts, United States
  • 2009
    • Compendia Bioscience
      Ann Arbor, Michigan, United States
  • 2002
    • Stanford University
      Palo Alto, California, United States