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Liu, Xiaole

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Xiaole

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Liu, Xiaole
Author's Publications: search.filters.isAuthorOfPublication.0416e1d5-1fb5-46f9-9b1d-7d1ceb31972e

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    Integrative Analysis of Pooled CRISPR Genetic Screens Using MAGeCKFlute
    (Springer Science and Business Media LLC, 2019-02-01) Wang, Binbin; Wang, Mei; Zhang, Wubing; Xiao, Tengfei; Chen, Chen-Hao; Wu, Alexander; Wu, Feizhen; Traugh, Nicole; Wang, Xiaoqing; Li, Ziyi; Mei, Shenglin; Cui, Yingbo; Shi, Sailing; Lipp, Jesse Jonathan; Hinterndorfer, Matthias; Zuber, Johannes; Brown, Myles; Li, Wei; Liu, Xiaole
    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 being a comprehensive pipeline that contains a series of functions for analyzing CRISPR screen data. This protocol explains how to use MAGeCKFlute to perform quality control, normalization, batch effect removal, copy number bias correction, gene hit identification, and downstream functional enrichment analysis for CRISPR screens. We also describe gene identification and data analysis in CRISPR screens involving drug treatment. Completing the entire MAGeCKFlute pipeline requires approximately two hours on a desktop computer running Linux or Mac OS and with R support. The MAGeCKFlute package is available at http://www.bioconductor.org/packages/release/bioc/html/MAGeCKFlute.html.
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    REST and Stress Resistance in Ageing and Alzheimer’s Disease
    (Nature Publishing Group, 2014) Lu, Tao; Aron, Liviu; Zullo, Joseph; Pan, Ying; Kim, Haeyoung; Chen, Yiwen; Yang, Tun-Hsiang; Kim, Hyun-Min; Drake, Derek; Liu, Xiaole; Bennett, David A.; Colaiacovo, Monica; Yankner, Bruce
    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.
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    Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation
    (Proceedings of the National Academy of Sciences, 2014) Hsieh, Chen-Lin; Fei, Teng; Chen, Yiwen; Li, Tiantian; Gao, Yanfei; Wang, Xiaodong; Sun, Tong; Sweeney, Christopher; Lee, Gwo-Shu Mary; Chen, Shaoyong; Balk, Steven; Liu, Xiaole; Brown, Myles; Kantoff, Philip
    The androgen receptor (AR) is a key factor that regulates the behavior and fate of prostate cancer cells. The AR-regulated network is activated when AR binds enhancer elements and modulates specific enhancer–promoter looping. Kallikrein-related peptidase 3 (KLK3), which codes for prostate-specific antigen (PSA), is a well-known AR-regulated gene and its upstream enhancers produce bidirectional enhancer RNAs (eRNAs), termed KLK3e. Here, we demonstrate that KLK3e facilitates the spatial interaction of the KLK3 enhancer and the KLK2 promoter and enhances long-distance KLK2 transcriptional activation. KLK3e carries the core enhancer element derived from the androgen response element III (ARE III), which is required for the interaction of AR and Mediator 1 (Med1). Furthermore, we show that KLK3e processes RNA-dependent enhancer activity depending on the integrity of core enhancer elements. The transcription of KLK3e was detectable and its expression is significantly correlated with KLK3 \((R^2 = 0.6213, P < 5 × 10^{−11})\) and KLK2 \((R^2 = 0.5893, P < 5 × 10^{−10})\) in human prostate tissues. Interestingly, RNAi silencing of KLK3e resulted in a modest negative effect on prostate cancer cell proliferation. Accordingly, we report that an androgen-induced eRNA scaffolds the AR-associated protein complex that modulates chromosomal architecture and selectively enhances AR-dependent gene expression.
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    MethylPurify: tumor purity deconvolution and differential methylation detection from single tumor DNA methylomes
    (BioMed Central, 2014) Zheng, Xiaoqi; Zhao, Qian; Wu, Hua-Jun; Li, Wei; Wang, Haiyun; Meyer, Clifford; Qin, Qian Alvin; Xu, Han; Zang, Chongzhi; Jiang, Peng; Li, Fuqiang; Hou, Yong; He, Jianxing; Wang, Jun; Zhang, Peng; Zhang, Yong; Liu, Xiaole
    We propose a statistical algorithm MethylPurify that uses regions with bisulfite reads showing discordant methylation levels to infer tumor purity from tumor samples alone. MethylPurify can identify differentially methylated regions (DMRs) from individual tumor methylome samples, without genomic variation information or prior knowledge from other datasets. In simulations with mixed bisulfite reads from cancer and normal cell lines, MethylPurify correctly inferred tumor purity and identified over 96% of the DMRs. From patient data, MethylPurify gave satisfactory DMR calls from tumor methylome samples alone, and revealed potential missed DMRs by tumor to normal comparison due to tumor heterogeneity. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0419-x) contains supplementary material, which is available to authorized users.
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    TCF4 and CDX2, major transcription factors for intestinal function, converge on the same cis-regulatory regions
    (Proceedings of the National Academy of Sciences, 2010) Verzi, M. P.; Hatzis, Phillip Evangelos; Sulahian, R.; Philips, J.; Schuijers, J.; Shin, H.; Freed, E.; Lynch, J. P.; Dang, D. T.; Brown, Myles; Clevers, H.; Liu, Xiaole; Shivdasani, Ramesh
    Surprisingly few pathways signal between cells, raising questions about mechanisms for tissue-specific responses. In particular, Wnt ligands signal in many mammalian tissues, including the intestinal epithelium, where constitutive signaling causes cancer. Genome-wide analysis of DNA cis-regulatory regions bound by the intestine-restricted transcription factor CDX2 in colonic cells uncovered highly significant overrepresentation of sequences that bind TCF4, a transcriptional effector of intestinal Wnt signaling. Chromatin immunoprecipitation confirmed TCF4 occupancy at most such sites and co-occupancy of CDX2 and TCF4 across short distances. A region spanning the single nucleotide polymorphism rs6983267, which lies within a MYC enhancer and confers colorectal cancer risk in humans, represented one of many co-occupied sites. Co-occupancy correlated with intestine-specific gene expression and CDX2 loss reduced TCF4 binding. These results implicate CDX2 in directing TCF4 binding in intestinal cells. Co-occupancy of regulatory regions by signal-effector and tissue-restricted transcription factors may represent a general mechanism for ubiquitous signaling pathways to achieve tissue-specific outcomes.
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    Gene expression profiling of human breast tissue samples using SAGE-Seq
    (Cold Spring Harbor Laboratory Press, 2010) Wu, Z. J.; Meyer, Clifford; Choudhury, S.; Shipitsin, M.; Maruyama, R.; Bessarabova, M.; Nikolskaya, T.; Sukumar, S.; Schwartzman, A.; Liu, Jun; Polyak, Kornelia; Liu, Xiaole
    We present a powerful application of ultra high-throughput sequencing, SAGE-Seq, for the accurate quantification of normal and neoplastic mammary epithelial cell transcriptomes. We develop data analysis pipelines that allow the mapping of sense and antisense strands of mitochondrial and RefSeq genes, the normalization between libraries, and the identification of differentially expressed genes. We find that the diversity of cancer transcriptomes is significantly higher than that of normal cells. Our analysis indicates that transcript discovery plateaus at 10 million reads/sample, and suggests a minimum desired sequencing depth around five million reads. Comparison of SAGE-Seq and traditional SAGE on normal and cancerous breast tissues reveals higher sensitivity of SAGE-Seq to detect less-abundant genes, including those encoding for known breast cancer-related transcription factors and G protein–coupled receptors (GPCRs). SAGE-Seq is able to identify genes and pathways abnormally activated in breast cancer that traditional SAGE failed to call. SAGE-Seq is a powerful method for the identification of biomarkers and therapeutic targets in human disease.
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    Essential and Redundant Functions of Caudal Family Proteins in Activating Adult Intestinal Genes
    (American Society for Microbiology, 2011) Verzi, M. P.; Shin, H.; Ho, L.-L.; Liu, Xiaole; Shivdasani, Ramesh
    Transcription factors that potently induce cell fate often remain expressed in the induced organ throughout life, but their requirements in adults are uncertain and varied. Mechanistically, it is unclear if they activate only tissue-specific genes or also directly repress heterologous genes. We conditionally inactivated mouse Cdx2, a dominant regulator of intestinal development, and mapped its genome occupancy in adult intestinal villi. Although homeotic transformation, observed in Cdx2-null embryos, was absent in mutant adults, gene expression and cell morphology were vitally compromised. Lethality was significantly accelerated in mice lacking both Cdx2 and its homolog Cdx1, with particular exaggeration of defects in villus enterocyte differentiation. Importantly, Cdx2 occupancy correlated with hundreds of transcripts that fell but not with equal numbers that rose with Cdx loss, indicating a predominantly activating role at intestinal cis-regulatory regions. Integrated consideration of a transcription factor's mutant phenotype and cistrome hence reveals the continued and distinct requirement in adults of a critical developmental regulator that activates tissue-specific genes.
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    Inference of transcriptional regulation in cancers
    (Proceedings of the National Academy of Sciences, 2015) Jiang, Peng; Freedman, Matthew; Liu, Jun; Liu, Xiaole
    We developed an efficient and accurate computational framework, RABIT (regression analysis with background integration), and comprehensively integrated public transcription factor (TF)-binding profiles with TCGA tumor-profiling datasets in 18 cancer types. To systematically search for cancer-associated TFs, RABIT controls the effect of tumor-confounding factors on transcriptional regulation, such as copy number alteration, DNA methylation, and TF somatic mutation. Our predicted TF regulatory activity in tumors is highly consistent with the knowledge from cancer gene databases and reveals many previously unidentified cancer-associated TFs. We also analyzed RNA-binding protein regulation in cancer and demonstrated that RABIT is a general platform for predicting oncogenic gene expression regulators.
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    MM-ChIP enables integrative analysis of cross-platform and between-laboratory ChIP-chip or ChIP-seq data
    (Springer Science + Business Media, 2011) Chen, Yiwen; Meyer, Clifford; Liu, Tao; Li, Wei; Liu, Jun; Liu, Xiaole
    The ChIP-chip and ChIP-seq techniques enable genome-wide mapping of in vivo protein-DNA interactions and chromatin states. The cross-platform and between-laboratory variation poses a challenge to the comparison and integration of results from different ChIP experiments. We describe a novel method, MM-ChIP, which integrates information from cross-platform and between-laboratory ChIP-chip or ChIP-seq datasets. It improves both the sensitivity and the specificity of detecting ChIP-enriched regions, and is a useful meta-analysis tool for driving discoveries from multiple data sources.
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    Cell-type selective chromatin remodeling defines the active subset of FOXA1-bound enhancers
    (Cold Spring Harbor Laboratory Press, 2008) Eeckhoute, J.; Lupien, M.; Meyer, Clifford; Verzi, M. P.; Shivdasani, Ramesh; Liu, Xiaole; Brown, Myles
    Selective activity of a specific set of enhancers defines tissue-specific gene transcription. The pioneer factor FOXA1 has been shown to induce functional enhancer competency through chromatin openings. We have previously found that FOXA1 is recruited to thousands of regions across the genome of a given cell type. Here, we monitored the chromatin structure at FOXA1 binding sites on a chromosome-wide scale using formaldehyde assisted isolation of regulatory elements (FAIRE). Surprisingly, we find that a significant fraction of FOXA1-bound sites have a relatively closed chromatin conformation linked to a shift of the epigenetic signature toward repressive histone marks. Importantly, these sites are not correlated with gene expression in a given cell type suggesting that FOXA1 is required, but not sufficient, for the functional activity of bound enhancers. Interestingly, we find that a significant proportion of the inactive FOXA1-bound regulatory sites in one cell type are actually functional in another cellular context. We found that at least half of the FOXA1 binding sites from a given cell type are shared with another cell lineage. Mechanisms that restrict the activity of shared FOXA1-bound enhancers likely play a significant role in defining the cell-type-specific functions of FOXA1.