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Zhenyu Xuan

Publications and source records attributed to Zhenyu Xuan.

13 recordsLinked to original sources
PubMed2006

Pan-genome isolation of low abundance transcripts using SAGE tag.

The SAGE (serial analysis of gene expression) method is sensitive at detecting the lower abundance transcripts. More than a third of human SAGE tags identified are novel representing the low abundance unknown transcripts. Using the GLGI method (generation of longer 3' EST from SAGE tag for gene identification), we converted 1009 low-copy, human X chromosome-specific SAGE tags into 10210 3' ESTs. We identified 3418 unique 3' ESTs, 46% of which are novel and originated from the lower abundance transcripts. However, nearly all 3' ESTs were mapped to various regions across the genome but not X chromosome. Detailed analysis indicates that those 3' ESTs were isolated by SAGE tag mis-priming to the non-parent transcripts. Replacing SAGE tags with non-transcribed genomic DNA tags resulted in poor amplification, indicating that the sequence similarity between different transcripts contributed to the amplification. Our study shows the prevalence of novel low abundance transcripts that can be isolated efficiently through SAGE tags mis-priming.

Base Pair Mismatch↗
PubMed2006

Computational prediction of methylation status in human genomic sequences.

Epigenetic effects in mammals depend largely on heritable genomic methylation patterns. We describe a computational pattern recognition method that is used to predict the methylation landscape of human brain DNA. This method can be applied both to CpG islands and to non-CpG island regions. It computes the methylation propensity for an 800-bp region centered on a CpG dinucleotide based on specific sequence features within the region. We tested several classifiers for classification performance, including K means clustering, linear discriminant analysis, logistic regression, and support vector machine. The best performing classifier used the support vector machine approach. Our program (called hdfinder) presently has a prediction accuracy of 86%, as validated with CpG regions for which methylation status has been experimentally determined. Using hdfinder, we have depicted the entire genomic methylation patterns for all 22 human autosomes.

Algorithms↗
PubMed2006

A clustering property of highly-degenerate transcription factor binding sites in the mammalian genome.

Transcription factor binding sites (TFBSs) are short DNA sequences interacting with transcription factors (TFs), which regulate gene expression. Due to the relatively short length of such binding sites, it is largely unclear how the specificity of protein-DNA interaction is achieved. Here, we have performed a genome-wide analysis of TFBS-like sequences for the transcriptional repressor, RE1 Silencing Transcription Factor (REST), as well as for several other representative mammalian TFs (c-myc, p53, HNF-1 and CREB). We find a nonrandom distribution of inexact sites for these TFs, referred to as highly-degenerate TFBSs, that are enriched around the cognate binding sites. Comparisons among human, mouse and rat orthologous promoters reveal that these highly-degenerate sites are conserved significantly more than expected by random chance, suggesting their positive selection during evolution. We propose that this arrangement provides a favorable genomic landscape for functional target site selection.

Animals↗
PubMed2006

DNA motifs in human and mouse proximal promoters predict tissue-specific expression.

Comprehensive identification of cis-regulatory elements is necessary for accurately reconstructing gene regulatory networks. We studied proximal promoters of human and mouse genes with differential expression across 56 terminally differentiated tissues. Using in silico techniques to discover, evaluate, and model interactions among sequence elements, we systematically identified regulatory modules that distinguish elevated from inhibited expression in the corresponding transcripts. We used these putative regulatory modules to construct a single predictive model for each of the 56 tissues. These predictors distinguish tissue-specific elevated from inhibited expression with statistical significance in 80% of the tissues (45 of 56). The predictors also reveal synergy between cis-regulatory modules and explain large-scale tissue-specific differential expression. For testis and liver, the predictors include computationally predicted motifs. For most other tissues, the predictors reveal synergy between experimentally verified motifs and indicate genes that are regulated by similar tissue-specific machinery. The identification in proximal promoters of cis-regulatory modules with tissue-specific activity lays the groundwork for complete characterization and deciphering of cis-regulatory DNA code in mammalian genomes.

Animals↗
PubMed2005

Regulating gene expression through RNA nuclear retention.

Multiple mechanisms have evolved to regulate the eukaryotic genome. We have identified CTN-RNA, a mouse tissue-specific approximately 8 kb nuclear-retained poly(A)+ RNA that regulates the level of its protein-coding partner. CTN-RNA is transcribed from the protein-coding mouse cationic amino acid transporter 2 (mCAT2) gene through alternative promoter and poly(A) site usage. CTN-RNA is diffusely distributed in nuclei and is also localized to paraspeckles. The 3'UTR of CTN-RNA contains elements for adenosine-to-inosine editing, involved in its nuclear retention. Interestingly, knockdown of CTN-RNA also downregulates mCAT2 mRNA. Under stress, CTN-RNA is posttranscriptionally cleaved to produce protein-coding mCAT2 mRNA. Our findings reveal a role of the cell nucleus in harboring RNA molecules that are not immediately needed to produce proteins but whose cytoplasmic presence is rapidly required upon physiologic stress. This mechanism of action highlights an important paradigm for the role of a nuclear-retained stable RNA transcript in regulating gene expression.

3' Untranslated Regions↗
PubMed2005

Genome-wide promoter extraction and analysis in human, mouse, and rat.

Large-scale and high-throughput genomics research needs reliable and comprehensive genome-wide promoter annotation resources. We have conducted a systematic investigation on how to improve mammalian promoter prediction by incorporating both transcript and conservation information. This enabled us to build a better multispecies promoter annotation pipeline and hence to create CSHLmpd (Cold Spring Harbor Laboratory Mammalian Promoter Database) for the biomedical research community, which can act as a starting reference system for more refined functional annotations.

Animals↗
PubMed2005

TRED: a Transcriptional Regulatory Element Database and a platform for in silico gene regulation studies.

In order to understand gene regulation, accurate and comprehensive knowledge of transcriptional regulatory elements is essential. Here, we report our efforts in building a mammalian Transcriptional Regulatory Element Database (TRED) with associated data analysis functions. It collects cis- and trans-regulatory elements and is dedicated to easy data access and analysis for both single-gene-based and genome-scale studies. Distinguishing features of TRED include: (i) relatively complete genome-wide promoter annotation for human, mouse and rat; (ii) availability of gene transcriptional regulation information including transcription factor binding sites and experimental evidence; (iii) data accuracy is ensured by hand curation; (iv) efficient user interface for easy and flexible data retrieval; and (v) implementation of on-the-fly sequence analysis tools. TRED can provide good training datasets for further genome-wide cis-regulatory element prediction and annotation, assist detailed functional studies and facilitate the decipher of gene regulatory networks (http://rulai.cshl.edu/TRED).

Animals↗
PubMed2005

From worm to human: bioinformatics approaches to identify FOXO target genes.

Longevity regulatory genes include the Forkhead transcription factor FOXO, in addition to NAD-dependent histone deacetylase silent information regulator 2 (Sir2). The FOXO/DAF-16 family of transcription factors constitute an evolutionarily conserved subgroup within a larger family known as winged helix or Forkhead transcriptional regulators. Here we demonstrate how to identify FOXO target genes and their potential cis-regulatory binding sites in the promoters via bioinformatics approaches. These results provide new testable hypotheses for further experimental verifications.

Animals↗
PubMed2004

The mouse genome: experimental examination of gene predictions and transcriptional start sites.

The completion of the mouse and other mammalian genome sequences will provide necessary, but not sufficient, knowledge for an understanding of much of mouse biology at the molecular level. As a requisite next step in this process, the genes in mouse and their structure must be elucidated. In particular, knowledge of the transcriptional start site of these genes will be necessary for further study of their regulatory regions. To assess the current state of mouse genome annotation to support this activity, we identified several hundred gene predictions in mouse with varying levels of supporting evidence and tested them using RACE-PCR. Modifications were made to the procedure allowing pooling of RNA samples, resulting in a scaleable procedure. The results illustrate potential errors or omissions in the current 5' end annotations in 58% of the genes detected. In testing experimentally unsupported gene predictions, we were able to identify 58 that are not usually annotated as genes but produced spliced transcripts (approximately 25% success rate). In addition, in many genes we were able to detect novel exons not predicted by any gene prediction algorithms. In 19.8% of the genes detected in this study, multiple transcript species were observed. These data show an urgent need to provide direct experimental validation of gene annotations. Moreover, these results show that direct validation using RACE-PCR can be an important component of genome-wide validation. This approach can be a useful tool in the ongoing efforts to increase the quality of gene annotations, especially transcriptional start sites, in complex genomes.

Animals↗
PubMed2002

Computational comparison of two mouse draft genomes and the human golden path.

BACKGROUND: The availability of both mouse and human draft genomes has marked the beginning of a new era of comparative mammalian genomics. The two available mouse genome assemblies, from the public mouse genome sequencing consortium and Celera Genomics, were obtained using different clone libraries and different assembly methods. RESULTS: We present here a critical comparison of the two latest mouse genome assemblies. The utility of the combined genomes is further demonstrated by comparing them with the human 'golden path' and through a subsequent analysis of a resulting conserved sequence element (CSE) database, which allows us to identify over 6,000 potential novel genes and to derive independent estimates of the number of human protein-coding genes. CONCLUSION: The Celera and public mouse assemblies differ in about 10% of the mouse genome. Each assembly has advantages over the other: Celera has higher accuracy in base-pairs and overall higher coverage of the genome; the public assembly, however, has higher sequence quality in some newly finished bacterial artificial chromosome clone (BAC) regions and the data are freely accessible. Perhaps most important, by combining both assemblies, we can get a better annotation of the human genome; in particular, we can obtain the most complete set of CSEs, one third of which are related to known genes and some others are related to other functional genomic regions. More than half the CSEs are of unknown function. From the CSEs, we estimate the total number of human protein-coding genes to be about 40,000. This searchable publicly available online CSEdb will expedite new discoveries through comparative genomics.

Animals↗
PubMed2002

A complete sequence of the T. tengcongensis genome.

Thermoanaerobacter tengcongensis is a rod-shaped, gram-negative, anaerobic eubacterium that was isolated from a freshwater hot spring in Tengchong, China. Using a whole-genome-shotgun method, we sequenced its 2,689,445-bp genome from an isolate, MB4(T) (Genbank accession no. AE008691). The genome encodes 2588 predicted coding sequences (CDS). Among them, 1764 (68.2%) are classified according to homology to other documented proteins, and the rest, 824 CDS (31.8%), are functionally unknown. One of the interesting features of the T. tengcongensis genome is that 86.7% of its genes are encoded on the leading strand of DNA replication. Based on protein sequence similarity, the T. tengcongensis genome is most similar to that of Bacillus halodurans, a mesophilic eubacterium, among all fully sequenced prokaryotic genomes up to date. Computational analysis on genes involved in basic metabolic pathways supports the experimental discovery that T. tengcongensis metabolizes sugars as principal energy and carbon source and utilizes thiosulfate and element sulfur, but not sulfate, as electron acceptors. T. tengcongensis, as a gram-negative rod by empirical definitions (such as staining), shares many genes that are characteristics of gram-positive bacteria whereas it is missing molecular components unique to gram-negative bacteria. A strong correlation between the G + C content of tDNA and rDNA genes and the optimal growth temperature is found among the sequenced thermophiles. It is concluded that thermophiles are a biologically and phylogenetically divergent group of prokaryotes that have converged to sustain extreme environmental conditions over evolutionary timescale.

Bacillaceae↗
PubMed2002

GFScan: a gene family search tool at genomic DNA level.

We have developed GFScan(Gene Family Scan), a tool that identifies members of a gene family by searching genomic DNA sequences with genomic DNA motifs (or matrices) that are representative of the family. We have tested GFScan on four human gene families including the neurotransmitter-gated ion-channels (NGIC) family, the carbonic anhydrases (CA) family, the Dbl homology (DH) domain family, and the ETS-domain family. All known members of these families with motifs mapped to sequenced genomic DNA regions were found, whereas some novel genomic locations were also found to match the motifs, which may indicate new members in these families. Compared with other methods, GFScan recognized all true positives with much fewer false positives. We also showed that motifs constructed based on human genes could be used to search the mouse genome to identify orthologous family members in mouse. This program is available at http://www.cshl.org/mzhanglab/.

Amino Acid Sequence↗