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Author

Haixia Li

Other affiliations: Genome Institute of Singapore
Bio: Haixia Li is an academic researcher from Agency for Science, Technology and Research. The author has contributed to research in topics: Zebrafish & Bivalent chromatin. The author has an hindex of 4, co-authored 5 publications receiving 1552 citations. Previous affiliations of Haixia Li include Genome Institute of Singapore.

Papers
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Journal ArticleDOI
05 Nov 2009-Nature
TL;DR: It is proposed that chromatin interactions constitute a primary mechanism for regulating transcription in mammalian genomes and is described as a new strategy, chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) for the de novo detection of global Chromatin interactions.
Abstract: Genomes are organized into high-level three-dimensional structures, and DNA elements separated by long genomic distances can in principle interact functionally Many transcription factors bind to regulatory DNA elements distant from gene promoters Although distal binding sites have been shown to regulate transcription by long-range chromatin interactions at a few loci, chromatin interactions and their impact on transcription regulation have not been investigated in a genome-wide manner Here we describe the development of a new strategy, chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) for the de novo detection of global chromatin interactions, with which we have comprehensively mapped the chromatin interaction network bound by oestrogen receptor α (ER-α) in the human genome We found that most high-confidence remote ER-α-binding sites are anchored at gene promoters through long-range chromatin interactions, suggesting that ER-α functions by extensive chromatin looping to bring genes together for coordinated transcriptional regulation We propose that chromatin interactions constitute a primary mechanism for regulating transcription in mammalian genomes © 2009 Macmillan Publishers Limited All rights reserved

1,602 citations

Journal ArticleDOI
TL;DR: This study presents an effective, high-throughput strategy of capturing molecular snapshots of chemical-induced biological states of a whole adult vertebrate that provides information on biomarkers of effects, deregulated signaling pathways, and possible affected biological functions, perturbed physiological systems, and increased health risks.
Abstract: The ability to perform large-scale, expression-based chemogenomics on whole adult organisms, as in invertebrate models (worm and fly), is highly desirable for a vertebrate model but its feasibility and potential has not been demonstrated. We performed expression-based chemogenomics on the whole adult organism of a vertebrate model, the zebrafish, and demonstrated its potential for large-scale predictive and discovery chemical biology. Focusing on two classes of compounds with wide implications to human health, polycyclic (halogenated) aromatic hydrocarbons [P(H)AHs] and estrogenic compounds (ECs), we generated robust prediction models that can discriminate compounds of the same class from those of different classes in two large independent experiments. The robust expression signatures led to the identification of biomarkers for potent aryl hydrocarbon receptor (AHR) and estrogen receptor (ER) agonists, respectively, and were validated in multiple targeted tissues. Knowledge-based data mining of human homologs of zebrafish genes revealed highly conserved chemical-induced biological responses/effects, health risks, and novel biological insights associated with AHR and ER that could be inferred to humans. Thus, our study presents an effective, high-throughput strategy of capturing molecular snapshots of chemical-induced biological states of a whole adult vertebrate that provides information on biomarkers of effects, deregulated signaling pathways, and possible affected biological functions, perturbed physiological systems, and increased health risks. These findings place zebrafish in a strategic position to bridge the wide gap between cell-based and rodent models in chemogenomics research and applications, especially in preclinical drug discovery and toxicology.

77 citations

Journal ArticleDOI
TL;DR: This study provides first evidence of molecular conservation of estrogen-responsiveness between zebrafish and human cancer cell lines, hence demonstrating the potential of zebra fish for estrogen-related cancer research and suggesting that estrogen regulation of cell cycle is perhaps one of the earliest forms of steroidal-receptor controlled cellular processes.
Abstract: The zebrafish is recognized as a versatile cancer and drug screening model. However, it is not known whether the estrogen-responsive genes and signaling pathways that are involved in estrogen-dependent carcinogenesis and human cancer are operating in zebrafish. In order to determine the potential of zebrafish model for estrogen-related cancer research, we investigated the molecular conservation of estrogen responses operating in both zebrafish and human cancer cell lines. Microarray experiment was performed on zebrafish exposed to estrogen (17β-estradiol; a classified carcinogen) and an anti-estrogen (ICI 182,780). Zebrafish estrogen-responsive genes sensitive to both estrogen and anti-estrogen were identified and validated using real-time PCR. Human homolog mapping and knowledge-based data mining were performed on zebrafish estrogen responsive genes followed by estrogen receptor binding site analysis and comparative transcriptome analysis with estrogen-responsive human cancer cell lines (MCF7, T47D and Ishikawa). Our transcriptome analysis captured multiple estrogen-responsive genes and signaling pathways that increased cell proliferation, promoted DNA damage and genome instability, and decreased tumor suppressing effects, suggesting a common mechanism for estrogen-induced carcinogenesis. Comparative analysis revealed a core set of conserved estrogen-responsive genes that demonstrate enrichment of estrogen receptor binding sites and cell cycle signaling pathways. Knowledge-based and network analysis led us to propose that the mechanism involving estrogen-activated estrogen receptor mediated down-regulation of human homolog HES1 followed by up-regulation cell cycle-related genes (human homologs E2F4, CDK2, CCNA, CCNB, CCNE), is highly conserved, and this mechanism may involve novel crosstalk with basal AHR. We also identified mitotic roles of polo-like kinase as a conserved signaling pathway with multiple entry points for estrogen regulation. The findings demonstrate the use of zebrafish for characterizing estrogen-like environmental carcinogens and anti-estrogen drug screening. From an evolutionary perspective, our findings suggest that estrogen regulation of cell cycle is perhaps one of the earliest forms of steroidal-receptor controlled cellular processes. Our study provides first evidence of molecular conservation of estrogen-responsiveness between zebrafish and human cancer cell lines, hence demonstrating the potential of zebrafish for estrogen-related cancer research.

37 citations

Journal ArticleDOI
01 Dec 2010
TL;DR: It is proved that the statistical distributions of KS-statistic under null hypothesis in variance un-normalised and normalised data settings are central and doubly non-central F-distributions, respectively.
Abstract: Kostka and Spang proposed a statistic (KS-statistic) and an algorithm (KS algorithm) to elicit Differentially Co-expressed Gene Sets (DCEGSs) by minimising KS-statistic. We prove that the statistical distributions of KS-statistic under null hypothesis in variance un-normalised and normalised data settings are central and doubly non-central F-distributions, respectively. Based on this analysis, we propose two alternative but equivalent statistics whose null distributions are easier to evaluate. Further, we propose to improve the algorithm by objectively setting the search parameters via maximising the statistical significance of the resultant gene set and pre-filtering the genes by Friendly Neighbours (FNs) algorithm.

5 citations

01 Jan 2006
TL;DR: A two stage algorithm, based on friendly neighbors (FNs) algorithm, called FNs-KS algorithm is proposed for improved discovery of differentially coexpressed gene-sets i.e. improves both sensitivity and specificity of the discovery.
Abstract: Differential co-expression signifies the deregulated pathways as opposed to differential expression that signifies change of gene expression. Kostka and Spang proposed a score and an algorithm to elicit differentially co-expressed gene-sets. We analyze the statistical properties of their score in two different data processing settings and obtain respective null-distributions to provide the statistical significance of a gene-set through the p-value of its score. We propose to use these p-values to automate their algorithm. In addition, we propose a two stage algorithm, based on Friendly Neighbors (FNs) algorithm, called FNs-KS algorithm for improved discovery of such gene set i.e. improves both sensitivity and specificity of the discovery.

Cited by
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Journal ArticleDOI
06 Sep 2012-Nature
TL;DR: The Encyclopedia of DNA Elements project provides new insights into the organization and regulation of the authors' genes and genome, and is an expansive resource of functional annotations for biomedical research.
Abstract: The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.

13,548 citations

Journal ArticleDOI
18 Dec 2014-Cell
TL;DR: In situ Hi-C is used to probe the 3D architecture of genomes, constructing haploid and diploid maps of nine cell types, identifying ∼10,000 loops that frequently link promoters and enhancers, correlate with gene activation, and show conservation across cell types and species.

5,945 citations

Journal ArticleDOI
TL;DR: Cuffdiff 2, an algorithm that estimates expression at transcript-level resolution and controls for variability evident across replicate libraries, robustly identifies differentially expressed transcripts and genes and reveals differential splicing and promoter-preference changes.
Abstract: Differential analysis of gene and transcript expression using high-throughput RNA sequencing (RNA-seq) is complicated by several sources of measurement variability and poses numerous statistical challenges. We present Cuffdiff 2, an algorithm that estimates expression at transcript-level resolution and controls for variability evident across replicate libraries. Cuffdiff 2 robustly identifies differentially expressed transcripts and genes and reveals differential splicing and promoter-preference changes. We demonstrate the accuracy of our approach through differential analysis of lung fibroblasts in response to loss of the developmental transcription factor HOXA1, which we show is required for lung fibroblast and HeLa cell cycle progression. Loss of HOXA1 results in significant expression level changes in thousands of individual transcripts, along with isoform switching events in key regulators of the cell cycle. Cuffdiff 2 performs robust differential analysis in RNA-seq experiments at transcript resolution, revealing a layer of regulation not readily observable with other high-throughput technologies.

3,319 citations

01 Sep 2012
TL;DR: The Encyclopedia of DNA Elements project provides new insights into the organization and regulation of the authors' genes and genome, and is an expansive resource of functional annotations for biomedical research.

2,767 citations

Journal ArticleDOI
03 Feb 2012-Cell
TL;DR: A high-resolution chromosomal contact map derived from a modified genome-wide chromosome conformation capture approach applied to Drosophila embryonic nuclei is presented, laying the foundation for detailed studies of chromosome structure and function in a genetically tractable system.

1,817 citations