Demo Faculty

163 articles

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Mar 2019 • Nature protocols

Integrative analysis of pooled CRISPR genetic screens using MAGeCKFlute

Binbin Wang, Mei Wang, Wubing Zhang, Tengfei Xiao, Chen-Hao Chen, Alexander Wu, Feizhen Wu, Nicole Traugh, Xiaoqing Wang, Ziyi Li, Shenglin Mei, Yingbo Cui, Sailing Shi, Jesse Jonathan Lipp, Matthias Hinterndorfer, Johannes Zuber, Myles Brown, Wei Li, X Shirley Liu

Genome-wide screening using CRISPR coupled with nuclease Cas9 (CRISPR–Cas9) is a powerful technology for the systematic evaluation of gene function. Statistically principled analysis is needed for the accurate identification of gene hits and associated pathways. Here, we describe how to perform computational analysis of CRISPR screens using the MAGeCKFlute pipeline. MAGeCKFlute combines the MAGeCK and MAGeCK-VISPR algorithms and incorporates additional downstream analysis functionalities. MAGeCKFlute is distinguished from other currently available tools by its comprehensive pipeline, which contains a series of functions for analyzing CRISPR screen data. This protocol explains how to use MAGeCKFlute to perform quality control (QC), normalization, batch effect removal, copy-number bias correction, gene hit identification and downstream functional enrichment analysis for CRISPR …

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Mar 2019 • Cancer cell

ARv7 represses Tumor-Suppressor genes in Castration-Resistant prostate cancer

Laura Cato, Jonas de Tribolet-Hardy, Irene Lee, Jaice T Rottenberg, Ilsa Coleman, Diana Melchers, René Houtman, Tengfei Xiao, Wei Li, Takuma Uo, Shihua Sun, Nane C Kuznik, Bettina Göppert, Fatma Ozgun, Martin E Van Royen, Adriaan B Houtsmuller, Raga Vadhi, Prakash K Rao, Lewyn Li, Steven P Balk, Robert B Den, Bruce J Trock, R Jeffrey Karnes, Robert B Jenkins, Eric A Klein, Elai Davicioni, Friederike J Gruhl, Henry W Long, X Shirley Liu, Andrew CB Cato, Nathan A Lack, Peter S Nelson, Stephen R Plymate, Anna C Groner, Myles Brown

Androgen deprivation therapy for prostate cancer (PCa) benefits patients with early disease, but becomes ineffective as PCa progresses to a castration-resistant state (CRPC). Initially CRPC remains dependent on androgen receptor (AR) signaling, often through increased expression of full-length AR (ARfl) or expression of dominantly active splice variants such as ARv7. We show in ARv7-dependent CRPC models that ARv7 binds together with ARfl to repress transcription of a set of growth-suppressive genes. Expression of the ARv7-repressed targets and ARv7 protein expression are negatively correlated and predicts for outcome in PCa patients. Our results provide insights into the role of ARv7 in CRPC and define a set of potential biomarkers for tumors dependent on ARv7.

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Feb 2019 • American Association for Cancer Research

Abstract A176: Overcoming CD8 T-cell suppression in the tumor microenvironment

Adam NR Cartwright, Peng Jiang, Assieh Saadatpour, Guo-Cheng Yuan, Shirley X Liu, Kai W Wucherpfennig

CD8 T-cell-mediated antitumor immunity is required for the control and elimination of tumors. However, tumors are able to overcome immune response resulting in immunosuppression, tumor growth, and metastatic spread. CD8 T-cells are controlled through a homeostatic network of positive and negative feedback loops. These negative signals are exploited by the tumor and associated suppressive cell populations in the tumor microenvironment. Immunotherapies targeted to receptors that control these negative signals, termed immune checkpoint inhibitors, have provided robust and durable responses to a number of cancers. Unfortunately, only a subset of patients will respond to current immunotherapies. This is due to the accruement of suppressive and inhibitory mechanisms employed by the tumor and its microenvironment. These include expression of inhibitory ligands, release of immune-suppressive factors …

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Jan 2019 • bioRxiv

Inferring transcriptional regulators through integrative modeling of public chromatin accessibility and ChIP-seq data

Qian Qin, Jingyu Fan, Rongbin Zheng, Changxin Wan, Shenglin Mei, Qiu Wu, Hanfei Sun, Jing Zhang, Myles Brown, Clifford A Meyer, X Shirley Liu

We developed Lisa (http://lisa.cistrome.org) to predict the transcriptional regulators (TRs) of differentially expressed or co-expressed gene sets. Based on the input gene sets, Lisa first uses compendia of public histone mark ChIP-seq and chromatin accessibility profiles to construct a chromatin model related to the regulation of these genes. Then using TR ChIP-seq peaks or imputed TR binding sites, Lisa probes the chromatin models using in silico deletion to find the most relevant TRs. Applied to gene sets derived from targeted TF perturbation experiments, Lisa boosted the performance of imputed TR cistromes, and outperformed alternative methods in identifying the perturbed TRs.

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Jan 2019 • Nucleic acids research

Cistrome Data Browser: expanded datasets and new tools for gene regulatory analysis

Rongbin Zheng, Changxin Wan, Shenglin Mei, Qian Qin, Qiu Wu, Hanfei Sun, Chen-Hao Chen, Myles Brown, Xiaoyan Zhang, Clifford A Meyer, X Shirley Liu

The Cistrome Data Browser (DB) is a resource of human and mouse cis-regulatory information derived from ChIP-seq, DNase-seq and ATAC-seq chromatin profiling assays, which map the genome-wide locations of transcription factor binding sites, histone post-translational modifications and regions of chromatin accessible to endonuclease activity. Currently, the Cistrome DB contains approximately 47,000 human and mouse samples with about 24,000 newly collected datasets compared to the previous release two years ago. Furthermore, the Cistrome DB has a new Toolkit module with several features that allow users to better utilize the large-scale ChIP-seq, DNase-seq, and ATAC-seq data. First, users can query the factors which are likely to regulate a specific gene of interest. Second, the Cistrome DB Toolkit facilitates searches for factor binding, histone modifications, and chromatin accessibility in any …

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Jan 2019 • Cancer Causes & Control, 1-13, 2019

Proceedings of the fourth international molecular pathological epidemiology (MPE) meeting

Peter T Campbell, Christine B Ambrosone, Reiko Nishihara, Hugo JWL Aerts, Melissa Bondy, Nilanjan Chatterjee, Montserrat Garcia-Closas, Marios Giannakis, Jeffrey A Golden, Yujing J Heng, N Sertac Kip, Jill Koshiol, X Shirley Liu, Camila M Lopes-Ramos, Lorelei A Mucci, Jonathan A Nowak, Amanda I Phipps, John Quackenbush, Robert E Schoen, Lynette M Sholl, Rulla M Tamimi, Molin Wang, Matty P Weijenberg, Catherine J Wu, Kana Wu, Song Yao, Kun-Hsing Yu, Xuehong Zhang, Timothy R Rebbeck, Shuji Ogino

An important premise of epidemiology is that individuals with the same disease share similar underlying etiologies and clinical outcomes. In the past few decades, our knowledge of disease pathogenesis has improved, and disease classification systems have evolved to the point where no complex disease processes are considered homogenous. As a result, pathology and epidemiology have been integrated into the single, unified field of molecular pathological epidemiology (MPE). Advancing integrative molecular and population-level health sciences and addressing the unique research challenges specific to the field of MPE necessitates assembling experts in diverse fields, including epidemiology, pathology, biostatistics, computational biology, bioinformatics, genomics, immunology, and nutritional and environmental sciences. Integrating these seemingly divergent fields can lead to a greater …

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Jan 2019 • Molecular Cancer Research

Targeting the MIF/CXCR7/AKT Signaling Pathway in Castration-Resistant Prostate Cancer

Shahrzad Rafiei, Bin Gui, Jiaxin Wu, X Shirley Liu, Adam S Kibel, Li Jia

Although androgen deprivation therapy (ADT) is an effective treatment for metastatic prostate cancer, incurable castration-resistant prostate cancer (CRPC) inevitably develops. Importantly, androgen receptor (AR) continues to be critical for prostate cancer growth and progression after ADT. One of the underlying molecular mechanisms is derepression of AR-repressed genes involved in cell cycle and proliferation after ADT. Here, the data demonstrate that C-X-C chemokine receptor type 7 (CXCR7), a seven-transmembrane G-protein–coupled chemokine receptor, is an AR-repressed gene and is upregulated after ADT. AR directly regulates CXCR7 using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) gene editing. Macrophage migration inhibitory factor (MIF) was identified as a ligand for CXCR7, which induces expression of cell-cycle genes through …

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2019 • Proc Natl Acad Sci U S A

Deciphering essential cistromes using genome-wide CRISPR screens.

Brown M* Fei T#, Li W#, Peng J#, Xiao T, Chen CH, Wu A, Huang J, Zang C, Liu XS*


2019 • Nat Genet

Landscape of B cell immunity and related immune evasion in human cancers.

Liu XS* Hu X#, Zhang J, Wang J, Fu J, Li T, Zheng X, Wang B, Gu S, Jiang P, Fan J, Ying X, Zhang J, Carroll MC, Wucherpfennig KW, Hacohen N, Zhang F, Zhang P, Liu JS*, Li B*

Tumor-infiltrating B cells are an important component in the microenvironment but have unclear anti-tumor effects. We enhanced our previous computational algorithm TRUST to extract the B cell immunoglobulin hypervariable regions from bulk tumor RNA-sequencing data. TRUST assembled more than 30 million complementarity-determining region 3 sequences of the B cell heavy chain (IgH) from The Cancer Genome Atlas. Widespread B cell clonal expansions and immunoglobulin subclass switch events were observed in diverse human cancers. Prevalent somatic copy number alterations in the MICA and MICB genes related to antibody-dependent cell-mediated cytotoxicity were identified in tumors with elevated B cell activity. The IgG3–1 subclass switch interacts with B cell–receptor affinity maturation and defects in the antibody-dependent cell-mediated cytotoxicity pathway. Comprehensive pancancer …

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2019 • Genome Medicine

Immune receptor repertoires in pediatric and adult acute myeloid leukemia.

Liu XS* Zhang J, Hu X, Wang J, Sahu AD, Cohen D, Song L, Ouyang Z, Fan J, Wang B, Fu J, Gu S, Sade-Feldman M, Hacohen N, Li W, Ying X*, Li B*


Dec 2018 • BMC bioinformatics

VIPER: Visualization Pipeline for RNA-seq, a Snakemake workflow for efficient and complete RNA-seq analysis

MacIntosh Cornwell, Mahesh Vangala, Len Taing, Zachary Herbert, Johannes Köster, Bo Li, Hanfei Sun, Taiwen Li, Jian Zhang, Xintao Qiu, Matthew Pun, Rinath Jeselsohn, Myles Brown, X Shirley Liu, Henry W Long

RNA sequencing has become a ubiquitous technology used throughout life sciences as an effective method of measuring RNA abundance quantitatively in tissues and cells. The increase in use of RNA-seq technology has led to the continuous development of new tools for every step of analysis from alignment to downstream pathway analysis. However, effectively using these analysis tools in a scalable and reproducible way can be challenging, especially for non-experts. Using the workflow management system Snakemake we have developed a user friendly, fast, efficient, and comprehensive pipeline for RNA-seq analysis. VIPER (Visualization Pipeline for RNA-seq analysis) is an analysis workflow that combines some of the most popular tools to take RNA-seq analysis from raw sequencing data, through alignment and quality control, into downstream differential expression and pathway analysis. VIPER has been created in a modular fashion to allow for the rapid incorporation of new tools to expand the capabilities. This capacity has already been exploited to include very recently developed tools that explore immune infiltrate and T-cell CDR (Complementarity-Determining Regions) reconstruction abilities. The pipeline has been conveniently packaged such that minimal computational skills are required to download and install the dozens of software packages that VIPER uses. VIPER is a comprehensive solution that performs most standard RNA-seq analyses quickly and effectively with a built-in capacity for customization and expansion.

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Nov 2018 • Nat Biotech. 36(11):1034.

Evaluation of immune repertoire inference methods from RNA-seq data.

Liu XS. Hu X, Zhang J, Liu JS, Li B


Oct 2018 • Nature medicine

Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response

Peng Jiang, Shengqing Gu, Deng Pan, Jingxin Fu, Avinash Sahu, Xihao Hu, Ziyi Li, Nicole Traugh, Xia Bu, Bo Li, Jun Liu, Gordon J Freeman, Myles A Brown, Kai W Wucherpfennig, X Shirley Liu

Cancer treatment by immune checkpoint blockade (ICB) can bring long-lasting clinical benefits, but only a fraction of patients respond to treatment. To predict ICB response, we developed TIDE, a computational method to model two primary mechanisms of tumor immune evasion: the induction of T cell dysfunction in tumors with high infiltration of cytotoxic T lymphocytes (CTL) and the prevention of T cell infiltration in tumors with low CTL level. We identified signatures of T cell dysfunction from large tumor cohorts by testing how the expression of each gene in tumors interacts with the CTL infiltration level to influence patient survival. We also modeled factors that exclude T cell infiltration into tumors using expression signatures from immunosuppressive cells. Using this framework and pre-treatment RNA-Seq or NanoString tumor expression profiles, TIDE predicted the outcome of melanoma patients treated with first-line …

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Sep 2018 • Journal of Vision

ChromaBlur: Rendering natural chromatic aberration drives accommodation effectively

Martin Banks, Steven Cholewiak, Gordon Love

Retinal-image blur occurs when the eye is focused at one distance and an object is at another. Vision scientists and computer-graphics engineers often wish to create images that reproduce such depth-dependent blur, but their method is incorrect because it does not incorporate the human eye's optical aberrations. We developed a rendering method that, by incorporating these aberrations, creates displayed images that produce more natural retinal images. Here we concentrate on one aberration: longitudinal chromatic aberration (LCA). LCA creates different chromatic effects in the retinal image for objects farther vs nearer than current focus. We asked whether one can drive eye focus (accommodation) by incorporating LCA into the rendering of objects meant to appear farther or nearer than current focus. Observers viewed textured planes monocularly in three conditions: 1) Real Change in which stimulus focal …

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Sep 2018 • Journal of Vision

Driving accommodation using simulated higher-order aberrations

Steven Cholewiak, Gordon Love, Martin Banks

The purpose of accommodation is to minimize blur. Defocus blur is the major source of blurring in the retinal image, but defocus blur itself cannot tell the eye if it is focused too near or too far. When the human eye is shown real blur, accommodation always changes in the correct direction without searching, so the visual system can somehow determine the sign of defocus. Potential signals for the sign include temporal fluctuations of accommodation (eg, microfluctuations), chromatic aberration, and higher-order aberrations (HOAs). We investigated whether simulated HOAs—specifically, astigmatism and spherical aberration—provide the needed sign information to drive accommodation in the right direction. Measurable astigmatism occurs in most people; its magnitude and axis varies across individuals. The point-spread function (PSF) of a defocused astigmatic eye is elliptical with the major axis in one direction when …

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Sep 2018 • Bioinformatics

SequencEnG: an Interactive Knowledge Base of Sequencing Techniques

Yi Zhang, Mohith Manjunath, Yeonsung Kim, Joerg Heintz, Jun S Song

summary Next-generation sequencing (NGS) techniques are revolutionizing biomedical research by providing powerful methods for generating genomic and epigenomic profiles. The rapid progress is posing an acute challenge to students and researchers to stay acquainted with the numerous available methods. We have developed an interactive online educational resource called Sequencing Techniques Engine for Genomics (SequencEnG) to provide a tree-structured knowledge base of 66 different sequencing techniques and step-by-step NGS data analysis pipelines comparing popular tools. SequencEnG is designed to facilitate barrier-free learning of current NGS techniques and provides a user-friendly interface for searching through experimental and analysis methods. Availability and implementation SequencEnG is part of the project Knowledge Engine for Genomics …

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Sep 2018 • Journal of Vision

Creating correct blur and its effect on accommodation

Steven A Cholewiak, Gordon D Love, Martin S Banks

Blur occurs naturally when the eye is focused at one distance and an object is presented at another distance. Computer-graphics engineers and vision scientists often wish to create display images that reproduce such depth-dependent blur, but their methods are incorrect for that purpose. They take into account the scene geometry, pupil size, and focal distances, but do not properly take into account the optical aberrations of the human eye. We developed a method that, by incorporating the viewer's optics, yields displayed images that produce retinal images close to the ones that occur in natural viewing. We concentrated on the effects of defocus, chromatic aberration, astigmatism, and spherical aberration and evaluated their effectiveness by conducting experiments in which we attempted to drive the eye's focusing response (accommodation) through the rendering of these aberrations. We found that accommodation is not driven at all by conventional rendering methods, but that it is driven surprisingly quickly and accurately by our method with defocus and chromatic aberration incorporated. We found some effect of astigmatism but none of spherical aberration. We discuss how the rendering approach can be used in vision science experiments and in the development of ophthalmic/optometric devices and augmented-and virtual-reality displays.

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Aug 2018 • Blood, The Journal of the American Society of Hematology

Mass cytometry of Hodgkin lymphoma reveals a CD4+ regulatory T-cell–rich and exhausted T-effector microenvironment

Fathima Zumla Cader, Ron CJ Schackmann, Xihao Hu, Kirsty Wienand, Robert Redd, Bjoern Chapuy, Jing Ouyang, Nicole Paul, Evisa Gjini, Mikel Lipschitz, Philippe Armand, David Wu, Jonathan R Fromm, Donna Neuberg, X Shirley Liu, Scott J Rodig, Margaret A Shipp

In classical Hodgkin lymphoma (cHL), the host antitumor immune response is ineffective. Hodgkin Reed-Sternberg (HRS) cells have multifaceted mechanisms to evade the immune system, including 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) genetic alterations, overexpression of PD-1 ligands, and associated T-cell exhaustion and additional structural bases of aberrant antigen presentation. The clinical success of PD-1 blockade in cHL suggests that the tumor microenvironment (TME) contains reversibly exhausted T effector cells (Teffs). However, durable responses are observed in patients with β2-microglobulin/major histocompatibility complex (MHC) class I loss on HRS cells, raising the possibility of non-CD8+ T cell–mediated mechanisms of efficacy of PD-1 blockade. These observations highlight the need for a detailed analysis of the cHL TME. Using a customized time-of-flight mass cytometry panel, we …

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Aug 2018 • Interface focus

Colour, contours, shading and shape: flow interactions reveal anchor neighbourhoods

Benjamin Kunsberg, Daniel Holtmann-Rice, Emma Alexander, Steven Cholewiak, Roland Fleming, Steven W Zucker

Two dilemmas arise in inferring shape information from shading. First, depending on the rendering physics, images can change significantly with (even) small changes in lighting or viewpoint, while the percept frequently does not. Second, brightness variations can be induced by material effects—such as pigmentation—as well as by shading effects. Improperly interpreted, material effects would confound shading effects. We show how these dilemmas are coupled by reviewing recent developments in shape inference together with a role for colour in separating material from shading effects. Aspects of both are represented in a common geometric (flow) framework, and novel displays of hue/shape interaction demonstrate a global effect with interactions limited to localized regions. Not all parts of an image are perceptually equal; shape percepts appear to be constructed from image anchor regions.

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Jul 2018 • Cancer Research 78 (13 Supplement), 4679-4679, 2018

Rectal cancer-infiltrating T cells show clonal expansion associated with spatially restricted tolerogenic phenotypes

Livius Penter, Kerstin Dietze, Felix Aigner, Lars Bullinger, Thomas Blankenstein, Leo Hansmann

T cell infiltration correlates with prognosis and outcome in colorectal cancer regardless of the tumor stage. However, data on clonal expansion, phenotypes, functions, and spatial distribution of tumor-infiltrating T cells (TILs) are limited.We hypothesized that subsets of clonally expanded rectal cancer-associated T cells are specifically recruited into the tumor and show characteristic phenotypes and functions.Paired TILs and T cells from adjacent unaffected mucosa were isolated from five treatment-naïve rectal cancer patients. Although T cell immune phenotypes were heterogeneous, the frequencies of CD38+, PD-1+, and TIM-3+ cells were significantly higher in CD8+ TILs when compared to T cells from unaffected mucosa (p < 0.05). To track clonal expansion and phenotypes at the single cell level, we combined 13-parameter FACS single cell index sorting with next generation T cell receptor (TCR) and phenotype …

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