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PubMed2006

Genomic organization and molecular characterization of Clostridium difficile bacteriophage PhiCD119.

In this study, we have isolated a temperate phage (PhiCD119) from a pathogenic Clostridium difficile strain and sequenced and annotated its genome. This virus has an icosahedral capsid and a contractile tail covered by a sheath and contains a double-stranded DNA genome. It belongs to the Myoviridae family of the tailed phages and the order Caudovirales. The genome was circularly permuted, with no physical ends detected by sequencing or restriction enzyme digestion analysis, and lacked a cos site. The DNA sequence of this phage consists of 53,325 bp, which carries 79 putative open reading frames (ORFs). A function could be assigned to 23 putative gene products, based upon bioinformatic analyses. The PhiCD119 genome is organized in a modular format, which includes modules for lysogeny, DNA replication, DNA packaging, structural proteins, and host cell lysis. The PhiCD119 attachment site attP lies in a noncoding region close to the putative integrase (int) gene. We have identified the phage integration site on the C. difficile chromosome (attB) located in a noncoding region just upstream of gene gltP, which encodes a carrier protein for glutamate and aspartate. This genetic analysis represents the first complete DNA sequence and annotation of a C. difficile phage.

Bacteriophages↗
PubMed2006

Genome-wide distribution of yeast RNA polymerase II and its control by Sen1 helicase.

Functional engagement of RNA polymerase II (Pol II) with eukaryotic chromosomes is a fundamental and highly regulated biological process. Here we present a high-resolution map of Pol II occupancy across the entire yeast genome. We compared a wild-type strain with a strain bearing a substitution in the Sen1 helicase, which is a Pol II termination factor for noncoding RNA genes. The wild-type pattern of Pol II distribution provides unexpected insights into the mechanisms by which genes are repressed or silenced. Remarkably, a single amino acid substitution that compromises Sen1 function causes profound changes in Pol II distribution over both noncoding and protein-coding genes, establishing an important function of Sen1 in the regulation of transcription. Given the strong similarity of the yeast and human Sen1 proteins, our results suggest that progressive neurological disorders caused by substitutions in the human Sen1 homolog Senataxin may be due to misregulation of transcription.

Chromatin Immunoprecipitation↗
PubMed2006

Brain evolution and uniqueness in the human genome.

Despite an ever-expanding database of sequenced mammalian genomes to be mined for clues, the emergence of the unique human brain remains an evolutionary enigma. In their new study, trawl the human genome and those of other mammals in search of short conserved DNA elements that show extremely rapid evolution only in humans. As they report in a recent issue of Nature, their scan yielded a gene for a novel noncoding RNA that adopts a human-specific structure and may regulate neurodevelopment.

Animals↗
PubMed1994

Differentiation of vaccine and wild-type polioviruses using polymerase chain reaction and restriction enzyme analysis.

Genomic amplification followed by selective digestion of restriction enzymes was used to differentiate polioviruses. The method was based on conserved and variable components of the 5'-noncoding region. The differences between Sabin vaccine and wild-type viruses made it possible to identify rapidly an isolated poliovirus as vaccine-related or wild-type virus. A total of 60 isolates and strains were tested and all of them were correctly identified. This method is recommended as a sensitive, specific and rapid way to differentiate polioviruses in clinical isolates and environmental samples.

Base Sequence↗
PubMed2002

Comparative sequence analysis of the X-inactivation center region in mouse, human, and bovine.

We have sequenced to high levels of accuracy 714-kb and 233-kb regions of the mouse and bovine X-inactivation centers (Xic), respectively, centered on the Xist gene. This has provided the basis for a fully annotated comparative analysis of the mouse Xic with the 2.3-Mb orthologous region in human and has allowed a three-way species comparison of the core central region, including the Xist gene. These comparisons have revealed conserved genes, both coding and noncoding, conserved CpG islands and, more surprisingly, conserved pseudogenes. The distribution of repeated elements, especially LINE repeats, in the mouse Xic region when compared to the rest of the genome does not support the hypothesis of a role for these repeat elements in the spreading of X inactivation. Interestingly, an asymmetric distribution of LINE elements on the two DNA strands was observed in the three species, not only within introns but also in intergenic regions. This feature is suggestive of important transcriptional activity within these intergenic regions. In silico prediction followed by experimental analysis has allowed four new genes, Cnbp2, Ftx, Jpx, and Ppnx, to be identified and novel, widespread, complex, and apparently noncoding transcriptional activity to be characterized in a region 5' of Xist that was recently shown to attract histone modification early after the onset of X inactivation.

Animals↗
PubMed2002

Functional proteomics of breast cancer for signal pathway profiling and target discovery.

The near completion of human genome sequencing and the introduction of mass spectrometry combined with advanced bioinformatics for protein identification have led to the emergence of proteomics as a powerful tool for characterizing new markers and therapeutic targets. Breast cancer proteomics has already identified proteins of potential clinical interest, such as the molecular chaperone 14-3-3 sigma and the heat shock protein HSP90, and technological innovations such as large scale and high throughput analysis are now driving the field. Methods in functional proteomics have also been developed to study the intracellular signaling pathways that underlie the development of breast cancer cells. As illustrated by fibroblast growth factor-2 and the H19 noncoding oncogenic mRNA, proteomics is a pertinent approach to identify signaling proteins and to decipher the complex signaling circuitry involved in tumor growth and metastasis. Together with genomics, proteomics is now providing a way to define molecular processes involved in breast carcinogenesis and to identify new therapeutic targets. The next challenge will be the introduction of proteomics as a tool for the clinic, for the establishment of diagnosis, prognosis, and the monitoring of treatment; however, this ambitious goal still requires further technological progress in the field.

Breast Neoplasms↗
PubMed2004

CpG mutation rates in the human genome are highly dependent on local GC content.

CpG dinucleotides mutate at a high rate because cytosine is vulnerable to deamination, cytosines in CpG dinucleotides are often methylated, and deamination of 5-methylcytosine (5mC) produces thymidine. Previous experiments have shown that DNA melting is the rate-limiting step in cytosine deamination. Here we show, through the analysis of human single-nucleotide polymorphisms (SNPs), that the mutation rate produced by 5mC deamination is highly dependent on local GC content. In fact, linear regression analysis showed that the log(10) of the 5mC mutation rates (inferred from SNP frequencies) had slopes of -3 when graphed with respect to the GC content of neighboring sequences. This is the ideal slope that would be expected if the correlation between CpG underrepresentation and GC content had been solely caused by DNA melting. Moreover, this same result was obtained regardless of the SNP locations (all SNPs versus only SNPs in noncoding intergenic regions, excluding CpG islands) and regardless of the lengths over which GC content was calculated (SNP sequences with a modal length of 564 bp versus genomic contigs with a modal length of 163 kb). Several alternative interpretations are discussed.

Animals↗
PubMed1999

Molecular phylogeny of phi29-like phages and their evolutionary relatedness to other protein-primed replicating phages and other phages hosted by gram-positive bacteria.

The phi29-like phage genus of Podoviridae family contains phages B103, BS32, GA-1, M2, Nf, phi15, phi29, and PZA that all infect Bacillus subtilis. They have very similar morphology and their genomes consist of linear double-stranded DNA of approximately 20 kb. The nucleotide sequences of individual genomes or their parts determined thus far show that these phages evolved from a common ancestor. A terminal protein (TP) that is covalently bound to the DNA 5'-end primes DNA replication of these phages. The same mechanism of DNA replication is used by the Cp-1 related phages (also members of the Podoviridae family) and by the phage PRD1 (member of the Tectoviridae family). Based on the complete or partial genomic sequence data of these phages it was possible to analyze the evolutionary relationship within the phi29-like phage genus as well as to other protein-primed replicating phages. Noncoding regions containing origins of replication were used in the analysis, as well as amino acid sequences of DNA polymerases, and with the phi29-like phages also amino acid sequences of the terminal proteins and of the gene 17 protein product, an accessory component of bacteriophage DNA replicating machinery. Included in the analysis are also results of a comparison of these phage DNAs with the prophages present in the Bacillus subtilis genome. Based on this complex analysis we define and describe in more detail the evolutionary branches of phi29-like phages, one branch consisting of phages BS32, phi15, phi29, and PZA, the second branch composed of phages B103, M2, and Nf, and the third branch having phage GA-1 as its sole member. In addition, amino acid sequences of holins, proteins involved in phage lysis were used to extend the evolutionary study to other phages infecting Gram-positive bacteria. The analysis based on the amino acid sequences of holins showed several weak points in present bacteriophage classification.

Amino Acid Sequence↗
PubMed1996

The complete mitochondrial DNA sequence of Atlantic cod (Gadus morhua): relevance to taxonomic studies among codfishes.

We have determined the complete sequence of an Atlantic cod (Gadus morhua) mitochondrial genome. The 16,696-bp genome contains the same 37 mitochondrial structural genes found in all other vertebrates analyzed, in an organization similar to that of the placental mammals. The cod mitochondrial DNA (mtDNA) contains variable numbers of a 40-bp heteroplasmic tandem repeat motif located in the major noncoding region, and the sequence presented here includes four repeats. Comparison among the major noncoding region in mtDNAs from different codfishes, as well as different stock samples of Atlantic cod, reveals conserved sequence features. The central region of the noncoding region as well as a spacer region located between the tRNAThr and tRNAPro genes appear to be variable in sequence, and are good candidates for high-resolution markers in population studies. Atlantic cod is the first marine bony fish whose mitochondrial genome is completely sequenced.

Amino Acid Sequence↗
PubMed1983

The murine E alpha immune response gene.

We have isolated and sequenced cDNA and genomic clones of the murine E alpha gene, one of the immune response genes of the major histocompatibility complex. Comparison of our data with those recently reported for the human homolog DR alpha shows an identical intron-exon structure, and a good conservation of the protein-coding sequences, including the amino acids potentially involved in organizing the second external protein domain into an immunoglobulin-like fold. Noncoding sequences are less conserved, with the exception of the promoter region. Finally, we show that differential expression of the gene in various cell types appears to be transcriptionally regulated, and that genomic rearrangements do not seem necessary for expression.

Amino Acid Sequence↗
PubMed1991

Nucleotide sequence and genomic organization of Aedes densonucleosis virus.

Over 99% of the genome of Aedes densonucleosis virus was determined. Two types of the viral DNA were found that differ only in four nucleotides (nt) in the 5' noncoding part and whose sizes are 4009 nt (more copious) and 4012 nt, respectively. Both 146 nt at the 3' end and 164 nt at the 5' end could assume a similar T-shaped structure; but unlike the adeno-associated virus, Aedes DNA has a unique primary DNA sequence at each terminus. However, the crossarms of these structures are built of the same sequences. An imperfect direct repeat of 34 nt was observed in the 5' noncoding part. The plus strand has three large open reading frames (ORF): a left ORF, a right ORF, and a mid ORF (within the left ORF). The left ORF codes for the nonstructural protein NS-1 (97.5K) featured by an NTP-binding domain, and the right ORF encodes the both capsid proteins, the smaller of which (39K) is supposed to be derived from the larger one (40.5K) by proteolytic cleavage. There is also an ORF in the minus strand. The putative polypeptide coded by this ORF is extremely hydrophobic.

Aedes↗
PubMed2000

Imprinted H19 gene expression in embryogenesis and human cancer: the oncofetal connection.

Cancer cells resemble embryonal cells morphologically and share with them characteristics such as reduced differentiation, rapid proliferation rate, and increased motility. Genes expressed in embryogenesis, down-regulated with tissue maturation and reexpressed in cancer, are designated as oncofetal genes, and many of them are used as tumor markers. The H19 gene is an imprinted gene that is expressed from the maternal allele and functions as an RNA molecule. It is abundantly expressed in fetal life and down-regulated postnatally. We have shown oncofetal expression of H19 in human cancer. The study of H19 expression in testicular germ cell tumors of adolescents and young adults, which follow lines of differentiation of the conceptus, demonstrates dissociation between level of expression and monoallelic versus biallelic expression, which are two independent oncofetal characteristics of cancer. Expression of the maternally expressed H19 from the paternal allele in the villous cytotrophoblastic cells of the androgenetic complete hydatidiform mole is designated relaxation of imprinting. H19 is abundantly expressed in the fetal bladder mucosa and in carcinoma of the urinary bladder. It is a marker of early recurrence and may be used as a potential basis for gene therapy.

Alleles↗
PubMed1998

Sequence-specific methylation of the mouse H19 gene in embryonic cells deficient in the Dnmt-1 gene.

We have used Dnmtc/c ES cells that are homozygous for disruption of the DNA methyltransferase gene to address how de novo methylation is propagated and whether it is directed to specific sites in the early embryo. We examined the imprinted H19 gene and the specific-sequence region implicated as an "imprinting mark" to determine whether de novo methylation was occurring at a restricted set of sites. Since the "imprinting mark" was found to be methylated differentially at all stages of development, we reasoned that the sequence may still be a target for the de novo methylation activity found in the Dnmtc/c cells, even though the loss of maintenance the methylase activity renders the H19 promoter active. We used bisulfite genomic sequencing to determine the methylation state of the imprinted region of the H19 gene and found a low level of DNA methylation at specific single CpG sites in the upstream region of the imprinted H19 sequence in the Dnmtc/c mutant ES cells. Moreover, these CpG sites appeared to be favoured targets for further de novo methylation of neighbouring CpG sites in rescued ES cells, which possess apparently normal maintenance activity. Our data provide further evidence for a separate methylating activity in ES cells and indicate that this activity displays sequence specificity.

Animals↗
PubMed1998

Imprinted expression and methylation of the mouse H19 gene are conserved in extraembryonic lineages.

The imprinted H19 gene is hypomethylated on the active maternal allele and hypermethylated on the repressed paternal allele in the somatic tissues of mice and humans. We previously demonstrated that the paternal-specific methylation of a 2 kb region located between -2 and -4 kb relative to the start of transcription is maintained throughout murine development, and we thus propose that this region is crucial to determining the imprinted expression of H19. Here, we test the correlation between differential methylation and imprinted expression by analyzing the mouse H19 gene in the undermethylated extraembryonic tissues. During early and midpostimplantation stages, > 95% of the H19 RNA is derived from the maternal allele. Dissection of yolk sac revealed that the paternal allele is expressed at a low level in the viseral endoderm but is completely repressed in visceral mesoderm. Bisulfite methylation analysis of yolk sac DNA showed that the maternal allele was hypomethylated and that 95% of the paternally derived clones were hypermethylated. Thus in extraembryonic lineages, the majority of H19 DNA is differentially methylated. These results lend further support to the hypothesis that DNA methylation confers the imprint on H19.

Alleles↗
PubMed1999

Selective expression of liver and activation-regulated chemokine (LARC) in intestinal epithelium in mice and humans.

The liver and activation-regulated chemokine (LARC), also termed MIP-3alpha and Exodus, is a novel human CC chemokine with a selective chemotactic activity for lymphocytes and dendritic cells. Here we describe genomic and cDNA clones encoding the murine orthologue of LARC (mLARC). The gene consists of four exons and three introns. The 5'-noncoding region of about 400 bp contains typical TATA and CAAT boxes but no other potential regulatory elements so far described. The cDNA encodes a CC chemokine of 97 amino acid residues with the highest homology to human LARC (64% amino acid identity). The 3'-noncoding region contains as many as five potential mRNA destabilization signals. mLARC was strongly and transiently induced in the murine monocytoid cell line J774 by lipopolysaccharide (LPS) but not by cytokines such as TNF-alpha, IFN-gamma, IL-1beta or IL-4. In normal mice, mLARC mRNA was expressed selectively in intestinal tissues such as small intestine and colon. Upon treatment with LPS, mLARC expression was enhanced in intestinal tissues and induced in some lymphoid tissues such as lymph nodes. Because of alternative splicing, there are two types of transcripts encoding mLARC and its variant mLARCvar with and without an N-terminal alanine in the mature protein, respectively. Both types of transcripts appeared to be expressed in various mouse tissues. In situ hybridization revealed that epithelial cells of intestinal tissues, especially those lining lymphoid follicles, expressed mLARC. Localization of LARC mRNA in epithelial cells was also demonstrated in a human appendix. Furthermore, mLARC was efficiently chemotactic for cells such as gammadelta type T cells in intestinal epithelium and naive B cells in Peyer's patches. Thus, in both humans and mice, LARC may be physiologically involved in formation and function of the mucosal lymphoid tissues by attracting lymphocytes and dendritic cells toward epithelial cells.

Amino Acid Sequence↗
PubMed1999

Characterization of a genomic region encoding the 32-kDa dense granule antigen of Sarcocystis muris (Apicomplexa).

Two subgenomic libraries constructed from Sarcocystis muris total DNA were screened with a cDNA probe, specific for a 32-kDa protein associated with the dense granules. Two clones reacted positively and were isolated, gDG 32/1 and gDG 32/2. Genomic clone gDG32/1 and part of clone gDG 32/2 have been sequenced. The composite nucleotide sequence of these genomic clones comprises 4.34 kb. It contains a 5' region of 2.14 kb, a first coding region (222 bp, exon I), a noncoding region (608 bp, intron), a second coding region (660 bp, exon II), and a 3' region of 693 bp. The upstream region shows a eukaryotic promoter structure and a consensus sequence for the 5' and 3' splicing sites. Thus the open reading frame (ORF DG32) coding for the 32-kDa protein of the dense granules of S. muris cyst merozoites is interrupted by an intron. To our knowledge, dg32 is the first sarcosporidian mosaic gene to be characterized.

Amino Acid Sequence↗
PubMed1978

Nucleotide sequence of turnip yellow mosaic virus coat protein mRNA.

The primary structure of the coat protein messenger RNA of turnip yellow mosaic virus is presented. This sequence is the first complete nucleotide sequence of the coat protein messenger of a plant virus to be reported. The coding region, consisting of 567 nucleotides, is flanked by a 5' noncoding region of 19 nucleotides (not including the initiation codon and the cap structure) and by a 3' noncoding region of 109 nucleotides (including the termination signal). The coat protein mRNA has a base composition identical to that of the genome RNA with, in particular, the same high content in cytosine (38%). The codons that govern the incorporation of amino acids into the coat protein are nonrandomly utilized: is greater than 50% of the time the third base of the codons used is a cytosine. This pattern of codon preference is particularly marked for Leu, lle Val, Thr and Cys.

Base Sequence↗
PubMed2004

Genomic imprinting in disruptive spermatogenesis.

The possibility of imprinting disease transmission by assisted reproductive technologies has been raised after births of children with Angelman's and Beckwith-Wiedemann's syndromes. To investigate whether imprinting defects were associated with disturbed spermatogenesis, we studied two oppositely imprinted genes in spermatozoan DNA from normozoospermic and oligozoospermic patients. In the mesodermal specific transcript gene (MEST), bisulphite genomic sequencing showed that maternal imprinting was correctly erased in all 123 patients. However, methylation of the H19 gene did not change in any of 27 normozoospermic individuals (0%, 95% CI 0-13%), compared with methylation changes in eight moderate (17%, 8-31%, p=0.026) and 15 severe (30%, 18-45%, p=0.002) oligozoospermic patients. Our data suggest an association between abnormal genomic imprinting and hypospermatogenesis, and that spermatozoa from oligozoospermic patients carry a raised risk of transmitting imprinting errors.

Alleles↗