Sep 2019 • Journal of Vision
Steven A Cholewiak, Peter Shirley, Morgan McGuire, Martin S Banks
In computer-generated imagery and vision science, defocus blur is often rendered to simulate objects closer or farther than the focal plane. But depth-dependent optical effects, like longitudinal chromatic aberration (LCA), are not implemented in a physically correct manner. Recent evidence has shown that incorporating LCA into rendered images produces a powerful cue for driving accommodation and depth perception. But implementing correct LCA effects is computationally expensive. Applied implementations of defocus blur with LCA are possible, but require approximations in order to run in real-time. We investigated whether real-time implementation of blur with LCA using approximate blur kernels and simplified treatment of occlusions can still drive accommodation and improve perceived depth compared to conventional methods that do not incorporate LCA. We measured accommodative responses with an …
Show moreJul 2019 • Nucleic acids research
Shaojuan Li, Changxin Wan, Rongbin Zheng, Jingyu Fan, Xin Dong, Clifford A Meyer, X Shirley Liu
Characterizing the ontologies of genes directly regulated by a transcription factor (TF), can help to elucidate the TF’s biological role. Previously, we developed a widely used method, BETA, to integrate TF ChIP-seq peaks with differential gene expression (DGE) data to infer direct target genes. Here, we provide Cistrome-GO, a website implementation of this method with enhanced features to conduct ontology analyses of gene regulation by TFs in human and mouse. Cistrome-GO has two working modes: solo mode for ChIP-seq peak analysis; and ensemble mode, which integrates ChIP-seq peaks with DGE data. Cistrome-GO is freely available at http://go.cistrome.org/.
Show moreJul 2019 • Frontiers in Genetics, section Bioinformatics and Computational Biology
Y. Zhang, M. Manjunath, J. Yan, B.A. Baur, S. Zhang, S. Roy, J.S Song
Genome-wide association studies (GWAS) have hitherto identified several germline variants associated with cancer susceptibility, but the molecular functions of these risk modulators remain largely uncharacterized. Recent studies have begun to uncover the regulatory potential of non-coding GWAS SNPs by using epigenetic information in corresponding cancer cell types and matched normal tissues. However, this approach does not explore the potential effect of risk germline variants on other important cell types that constitute the microenvironment of tumor or its precursor. This paper presents evidence that the breast cancer-associated variant rs3903072 may regulate the expression of CTSW in tumor infiltrating lymphocytes. CTSW is a candidate tumor-suppressor gene, with expression highly specific to immune cells and also positively correlated with breast cancer patient survival. Integrative analyses suggest a putative causative variant in a GWAS-linked enhancer in lymphocytes that loops to the 3’ end of CTSW through three-dimensional chromatin interaction. Our work thus poses the possibility that a cancer-associated genetic variant could regulate a gene not only in the cell of cancer origin, but also in immune cells in the microenvironment, thereby modulating the immune surveillance by T lymphocytes and natural killer cells and affecting the clearing of early cancer initiating cells.
Show moreJul 2019 • Investigative Ophthalmology & Visual Science
Vivek Labhishetty, Steven Cholewiak, Martin S Banks
Purpose: Experiments suggest that hyperopic focus in the peripheral retina increases the risk of developing myopia. This implies that signed defocus can trigger eye growth. But does this mean blur in the periphery affects other oculomotor mechanisms such as accommodation? Stimulation of the human peripheral retina when no foveal stimulus is present elicits accommodation. But in natural viewing, the fovea and periphery are nearly always both stimulated. We investigated accommodative responses when the fovea and periphery are both stimulated, but with different signs of defocus.Methods: 10 participants (18-25 yrs) viewed black-white textures monocularly. The stimuli varied in depth (±1.5 D) sinusoidally (0.1, 0.2, 0.5, or 1.0 Hz). Three conditions were tested: Real Blur, Defocus+ LCA, and Defocus+ LCA Conflict. In Real Blur, the optical distance of the textures (disks subtending 1, 2, 4, 6, 8, or 14) was varied …
Show moreJun 2019 • Oncoimmunology
Livius Penter, Kerstin Dietze, Julia Ritter, Maria Fernanda Lammoglia Cobo, Josefin Garmshausen, Felix Aigner, Lars Bullinger, Holger Hackstein, Sandra Wienzek-Lischka, Thomas Blankenstein, Michael Hummel, Klaus Dornmair, Leo Hansmann
The degree and type of T cell infiltration influence rectal cancer prognosis regardless of classical tumor staging. We asked whether clonal expansion and tumor infiltration are restricted to selected-phenotype T cells; which clones are accessible in peripheral blood; and what the spatial distribution of their target antigens is.From five rectal cancer patients, we isolated paired tumor-infiltrating T cells (TILs) and T cells from unaffected rectum mucosa (TUM) using 13-parameter FACS single cell index sorting. TCRαβ sequences, cytokine, and transcription factor expression were determined with single cell sequencing. TILs and TUM occupied distinct phenotype compartments and clonal expansion predominantly occurred within CD8+ T cells. Expanded TIL clones identified by paired TCRαβ sequencing and exclusively detectable in the tumor showed characteristic PD-1 and TIM-3 expression. TCRβ repertoire sequencing …
Show moreJun 2019 • Nature genetics
Xihao Hu, Jian Zhang, Jin Wang, Jingxin Fu, Taiwen Li, Xiaoqi Zheng, Binbin Wang
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Show moreMay 2019 • University of Illinois at Urbana-Champaign, 2019
Yi Zhang
Genome-wide association studies have hitherto identified several common genetic variants that may significantly modulate cancer susceptibility. However, the precise molecular mechanisms behind these associations remain largely uncharacterized, creating barriers to understanding the biological processes behind oncogenesis. This thesis presents an integrated computational method for identifying functional regulatory variants associated with cancer and for revealing their precise gene-regulation role by combining analyses of heterogeneous high-throughput sequencing data. Application of the method to breast cancer susceptibility regions reveals functional variants and their perturbation on cis-regulatory elements that act on cancer-associated genes. It is also shown that a cancer-associated variant may interact with the tumor microenvironment. Overall, these computational methods built on multi-omics data have helped move toward the goal of understanding the genotype-phenotype association for personalized medicine.
Show moreMar 2019 • Cancer cell
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.
Show moreMar 2019 • Nature protocols
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 …
Show moreFeb 2019 • American Association for Cancer Research
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 …
Show moreJan 2019 • Nucleic acids research
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 …
Show moreJan 2019 • Cancer Causes & Control, 1-13, 2019
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 …
Show moreJan 2019 • Molecular Cancer Research
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 …
Show moreJan 2019 • bioRxiv
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.
Show moreJan 2019 • Molecular Cancer Research
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 …
Show more2019 • Genome Medicine
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*
2019 • Nat Genet
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 …
Show more2019 • Proc Natl Acad Sci U S A
Brown M* Fei T#, Li W#, Peng J#, Xiao T, Chen CH, Wu A, Huang J, Zang C, Liu XS*
Dec 2018 • BMC bioinformatics
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.
Show moreNov 2018 • Nature biotechnology
Xihao Hu, Jian Zhang, Jun S Liu, Bo Li, Xiaole Shirley Liu
To the Editor: Characterizing tumor-infiltrating T cell receptor (TCR) repertoire is a critical step toward identifying cancer antigens and developing new immunotherapies1. We previously developed a computational algorithm named TRUST2, 3 to extract TCR hypervariable complementarity-determining region 3 (CDR3) sequences from unselected bulk tumor RNA sequencing (RNA-seq) data. When applied to large cancer cohorts, TRUST found associations between tumor mutation load and TCR repertoires2. A recent study by Bolotin et al. 4 reported a new version of their MiXCR tool that enables assembly of TCR clonotypes from RNA-seq data. In comparing MiXCR to TRUST, Bolotin et al. 4 concluded that MiXCR was superior and that the output of TRUST includes unconfirmed and potentially false positive results. Here, we point out important differences between TRUST and MiXCR, as well as differences in …
Show moreNov 2018 • Nat Biotech. 36(11):1034.
Liu XS. Hu X, Zhang J, Liu JS, Li B