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PubMed1979

Sequence of the 16 S-23 s spacer region in two ribosomal RNA operons of Escherichia coli.

The transducing phages lambdadaroE and lambdadilv5, which carry the Escherichia coli ribosomal RNA operons rrnD and rrnX, respectively, have been mapped with the restriction endonucleases BamHI, EcoRI, HindIII, and Sma I. Using hybridization techniques, we have located the ribosomal RNA genes on these phage DNAs. The DNA sequence of the 437-base-pair 16 S-23 S ribosomal RNA intergenic spacer in the two rRNA operons rrnD and rrnX has been determined. The nucleotides examined exhibit only one base pair change between rrnD and rrnX. Both spacer regions contain the genes for tRNA1Ile and tRNA1BAla; the gene sequences are identical with the previously deduced tRNA sequences and are clustered within the first 60% of the spacer DNA. The most striking feature of the 16 S-23 S intergenic region in these two operons is the disparity in G-C content between the tRNA gene sequences (60% G-C) and the remaining spacer DNA (37% G-C). Spacer sequences are known to be involved in the processing of the ribosomal RNA transcript by RNase III and RNase P. In addition, we report the sequence of the first 108 base pairs of the 23 S rRNA gene.

Base Sequence↗
PubMed2024

Triphenyl Phosphate Alters Methyltransferase Expression and Induces Genome-Wide Aberrant DNA Methylation in Zebrafish Larvae.

Emerging environmental contaminants, organophosphate flame retardants (OPFRs), pose significant threats to ecosystems and human health. Despite numerous studies reporting the toxic effects of OPFRs, research on their epigenetic alterations remains limited. In this study, we investigated the effects of exposure to 2-ethylhexyl diphenyl phosphate (EHDPP), tricresyl phosphate (TMPP), and triphenyl phosphate (TPHP) on DNA methylation patterns during zebrafish embryonic development. We assessed general toxicity and morphological changes, measured global DNA methylation and hydroxymethylation levels, and evaluated DNA methyltransferase (DNMT) enzyme activity, as well as mRNA expression of DNMTs and ten-eleven translocation (TET) methylcytosine dioxygenase genes. Additionally, we analyzed genome-wide methylation patterns in zebrafish larvae using reduced-representation bisulfite sequencing. Our morphological assessment revealed no general toxicity, but a statistically significant yet subtle decrease in body length following exposure to TMPP and EHDPP, along with a reduction in head height after TPHP exposure, was observed. Eye diameter and head width were unaffected by any of the OPFRs. There were no significant changes in global DNA methylation levels in any exposure group, and TMPP showed no clear effect on DNMT expression. However, EHDPP significantly decreased only DNMT1 expression, while TPHP exposure reduced the expression of several DNMT orthologues and TETs in zebrafish larvae, leading to genome-wide aberrant DNA methylation. Differential methylation occurred primarily in introns (43%) and intergenic regions (37%), with 9% and 10% occurring in exons and promoter regions, respectively. Pathway enrichment analysis of differentially methylated region-associated genes indicated that TPHP exposure enhanced several biological and molecular functions corresponding to metabolism and neurological development. KEGG enrichment analysis further revealed TPHP-mediated potential effects on several signaling pathways including TGFβ, cytokine, and insulin signaling. This study identifies specific changes in DNA methylation in zebrafish larvae after TPHP exposure and brings novel insights into the epigenetic mode of action of TPHP.

Animals↗
PubMed1979

Construction of an M13 histidine-transducing phage: a single-stranded cloning vehicle with one EcoRI site.

In order to create a ready source of single-stranded DNA for DNA sequence determination by the dideoxy chain-termination method, the promoter-proximal part of the histidine operon, the hisOGD region of Salmonella typhimurium, was cloned onto the single-stranded phage M13. Both orientations of the his DNA were cloned to supply DNA template for sequencing of each strand. Insertion was achieved at an HaeIII site in the intergenic region (IR) of M13, and a single EcoRI site was purposely regenerated at one boundary of the his DNA insert. Infected colonies, not plaques, were selected using the hisD gene as a selective marker. The single RI site and the hisD marker for auxotrophic selection represent improvements on the wild type M13 as a single-stranded vector for cloning other DNA.

Base Sequence↗
PubMed2024

Multiple Forms and Functions of Premature Termination by RNA Polymerase II.

Eukaryotic genomes are widely transcribed by RNA polymerase II (pol II) both within genes and in intergenic regions. POL II elongation complexes comprising the polymerase, the DNA template and nascent RNA transcript must be extremely processive in order to transcribe the longest genes which are over 1 megabase long and take many hours to traverse. Dedicated termination mechanisms are required to disrupt these highly stable complexes. Transcription termination occurs not only at the 3' ends of genes once a full length transcript has been made, but also within genes and in promiscuously transcribed intergenic regions. Termination at these latter positions is termed "premature" because it is not triggered in response to a specific signal that marks the 3' end of a gene, like a polyA site. One purpose of premature termination is to remove polymerases from intergenic regions where they are "not wanted" because they may interfere with transcription of overlapping genes or the progress of replication forks. Premature termination has recently been appreciated to occur at surprisingly high rates within genes where it is speculated to serve regulatory or quality control functions. In this review I summarize current understanding of the different mechanisms of premature termination and its potential functions.

RNA Polymerase II↗
PubMed1978

Transposition of a DNA sequence determining kanamycin resistance into the single-stranded genome of bacteriophage fd.

Derivatives of bacteriophages fd which transduce kanamycin resistance were selected after growth of the phage in an E. coli strain that carried transpoon 5 (Tn5). Different clones of transducing phage and their DNAs were characterized by gel electrophoresis, electron microscopy, and by their ability to multiply in the absence of helper phage. Integration of the intact transposon into the full size phage genome was correlated with an increase in size of the phage particle from 0.95 mu to 1.7 mu, and with the appearance in the phage DNA of the stem loop structure characteristic for single-stranded Tn5 DNA. In non-defective phages the site of insertion was mapped by heteroduplex analysis within the intergenic region of the phage genome. Defective transducing phages were characterized as an insertion of Tn5 into a phage gene, and/or as a partial deletion or duplication of phage and transposon DNA. The size of the transducing phage from different defective clones varied from 0.6 mu to 3.0 mu and was directly proportional to the DNA content. These results demonstrate that filamentous bacteriophage are highly capable to replicate and package very different amounts of foreign DNA.

Coliphages↗
PubMed1978

Insertion of the Tn3 transposon into the genome of the single-stranded DNA phage M13.

The transposable genetic element Tn3, which carries an ampicillin (Ap) resistance determinant, has been translocated from a ColE1-Apr plasmid, RSF2124, to the genome of the filamentous single-stranded DNA phage M13. The site orientation of the inserted element has been determined for one such phage, M13::Tn3-15. The insertion is within the intergenic space separating genes 2 and 4 and containing both the viral strand and complementary strand origins. The lengths of both the filamentous phage and the duplex replicative form (RF) DNA are 1.7--1.8 times those of M13 phage and replicative form DNA. Both plaque formation and transduction of sensitive cells to ampicillin resistance by M13::Tn3-15 are sensitive to purified antibodies to the M13 major coat protein.

Ampicillin↗
PubMed1977

Filamentous coliphage M13 as a cloning vehicle: insertion of a HindII fragment of the lac regulatory region in M13 replicative form in vitro.

A HindII restriction fragment comprising the Escherichia coli lac regulatory region and the genetic information for the alpha peptide of beta-galactosidase (beta-D-galactosidegalactohydrolase, EC. 3.2.1.23) has been inserted into 1 of the 10 Bsu I cleavage sites of M13 by blunt end ligation. A stable hybrid phage was isolated and identified by its ability to complement the lac alpha function. Further characterization of the hybrid phage includes retransformation studies, agarose gel electrophoresis, DNA-DNA hybridization, and heteroduplex mapping. The insertion point has been localized at 0.083 map unit on thewild-type circular map-i.e., within the intergenic region. The results prove that part of the intergenic region is nonessential and that the phage can be used as a cloning vehicle.

Coliphages↗
PubMed1979

Multiple forms of inducible drug-metabolizing enzymes: a reasonable mechanism by which any organism can cope with adversity.

All organisms possess a number of genetically regulated mechanisms in order to cope with rapid adverse changes in the environment. The two systems which appear to respond to a seemingly endless array of chemical specificities are the immune response and the induction of drug-metabolizing enzymes. Similarities and differences between the immunoglobulin and the cytochrome P-450-mediated monooxygenase systems are described. DNA insertion sequences, plasmid "transposons," maize "controlling elements," gene duplication, intervening sequences, and high-frequency intergenic recombination are all discussed as possible methods by which organisms can "adapt" quickly to a new selective pressure. If the regulation of P-450 induction resembles in any way the other methods by which pro- and eukaryotes cope genetically with numerous forms of environmental adversity, therefore, it is very likely that mammalian tissues contain hundreds, if not thousands, of inducible forms of P-450.

Adaptation, Physiological↗
PubMed1979

Structure of the human G gamma-A gamma-delta-beta-globin gene locus.

We have constructed a physical map of the human G gamma-, A gamma-, delta-, and beta-globin genes. The previously described maps of the fetal and adult beta-like globin genes have been linked to one another by identification of a DNA fragment, generated by BamHI, that contains part of each of the A gamma- and delta-globin genes. The map obtained, which spans more than 40 kilobases, shows the following intergene distances: between G gamma and A gamma, 3500 base pairs; between A gamma and delta, 13,500 base pairs; and between delta and beta, 5500 base pairs. All genes are transcribed from the same DNA strand.

Adult↗
PubMed1979

Enhanced mitotic recombination in a ligase-defective mutant of the yeast Saccharomyces cerevisiae.

The temperature-sensitive Saccharomyces cerevisiae cell cycle mutant cdc9 is defective in DNA ligase, and the DNA synthesized at the restrictive temperature contains many single-strand breaks. We find that holding a diploid homozygous for cdc9 at the restrictive temperature and then plating cells at the permissive temperature gives rise to increased intragenic and intergenic recombination. In the latter case, recombinants signaled by the ade2 locus rise to about 4% of the survivors after 6 hr of incubation at the restrictive temperature. We propose that the single-strand breaks left in DNA synthesized at the restrictive temperature may lead to recombination.

Cell Cycle↗
PubMed1978

Multiple, heterogeneous actin genes in Dictyostelium.

We have used an actin gene-containing restriction fragment of plasmid M6 (Kindle and Firtel, 1978) to select a second actin gene-containing plasmid which we have named pDd actin 2. This plasmid has been shown to contain two actin genes separated by 350 bp of nonactin DNA. When heteroduplexes are formed between any two of the three actin genes present in chimeric plasmids, the region of homology is 1100 +/- 100 bp. This is close to the minimum length required to code for actin protein. The 1100 bp region of intergene homology corresponds to the 1100 bp homology observed between M6 and the two actin cDNA plasmids pcDd actin B1 and pcDd actin A1 (Bender et al., 1978). We have no evidence for additional sequences common to either the 3' or 5' ends of the 1100 +/- 100 bp region of intergene homology. Thermal denaturation experiments show that different pairs of actin genes are diverged from each other by as much as 6--8%. There are two size classes of mRNA complementary to the three actin genes. These have lenghts of 1.25 and 1.35 kb as determined on methyl mercuric hydroxide-containing agarose gels. The possible linkage of these three actin genes to other actin genes is discussed.

Actins↗
PubMed2022

Enhancer and super-enhancer landscape in polycystic kidney disease.

Widespread aberrant gene expression is a pathological hallmark of polycystic kidney disease (PKD). Numerous pathogenic signaling cascades, including c-Myc, Fos, and Jun, are transactivated. However, the underlying epigenetic regulators are poorly defined. Here we show that H3K27ac, an acetylated modification of DNA packing protein histone H3 that marks active enhancers, is elevated in mouse and human samples of autosomal dominant PKD. Using comparative H3K27ac ChIP-Seq analysis, we mapped over 16000 active intronic and intergenic enhancer elements in Pkd1-mutant mouse kidneys. We found that the cystic kidney epigenetic landscape resembles that of a developing kidney, and over 90% of upregulated genes in Pkd1-mutant kidneys are co-housed with activated enhancers in the same topologically associated domains. Furthermore, we identified an evolutionarily conserved enhancer cluster downstream of the c-Myc gene and super-enhancers flanking both Jun and Fos loci in mouse and human models of autosomal dominant PKD. Deleting these regulatory elements reduced c-Myc, Jun, or Fos abundance and suppressed proliferation and 3D cyst growth of Pkd1-mutant cells. Finally, inhibiting glycolysis and glutaminolysis or activating Ppara in Pkd1-mutant cells lowerd global H3K27ac levels and its abundance on c-Myc enhancers. Thus, our work suggests that epigenetic rewiring mediates the transcriptomic dysregulation in PKD, and the regulatory elements can be targeted to slow cyst growth.

Animals↗
PubMed1978

Nucleotide sequence of bacteriophage G4 DNA.

The 5,577 nucleotide long sequence of bacteriophage G4 DNA has been determined using the 'plus and minus' and chain termination methods of DNA sequencing. This sequence has been compared with that of the closely related bacteriophage phiX174 (refs 1, 55). In the coding regions there is an average of 33.1% nucleotide sequence differences between the two genomes, but the distribution of these changes is not random and the sequence of some genes is more conserved than others. There is less sequence similarity between the untranslated intergenic regions of G4 and phiX174, but despite this the sequences of the J/F, F/G and H/A untranslated spaces in both genomes have similar sized hairpin loops, which may be related to their function.

Bacteriophages↗
PubMed2026

Overexpression of a subset of long intergenic noncoding RNAs in uterine serous carcinoma predicts poor prognosis.

The evaluation and prediction of uterine serous carcinoma (USC), a type of endometrial cancer that is more severe than endometrioid adenocarcinoma, remain challenging. Long noncoding RNAs (lncRNAs) are frequently dysregulated in human cancers. This study assessed the expression patterns and prognostic values of long intergenic noncoding RNAs (lincRNAs) in USC. RNA sequencing, copy number variation (CNV), and clinical data from The Cancer Genome Atlas were used to investigate various lncRNAs in endometrial cancer. LincRNAs, a major subclass of lncRNAs, exhibit specific expression patterns modulated by CNVs and act as predictors of poor prognosis, survival, and recurrence in USC. Functional analyses were conducted to investigate the roles of lncRNAs in USC. Finally, the expression of these lincRNAs was verified in 32 pairs of USCs collected from the hospital over 3 years. A series of lincRNAs were found to be specifically expressed in USC compared with other lncRNAs and regulated by CNV. Moreover, these specific upregulated lincRNAs, particularly ENSG00000281406, ENSG00000226791, ENSG00000269903, and ENSG00000204277, demonstrated poor prognoses for survival and recurrence in USC. Functionally, our analysis showed that ENSG00000281406 positively correlated with the Wnt signaling pathway, whereas ENSG00000226791, ENSG00000269903, and ENSG00000204277 negatively correlated with the T-cell receptor signaling pathway. Importantly, we confirmed that ENSG00000204277 negatively correlated with CD8+ T-cell immune infiltration in USC. Our results highlight that these lincRNAs can serve as new biomarkers for the prognostic prediction of USC. In particular, ENSG00000204277 may be used as a therapeutic target for USC.

Humans↗
PubMed2026

Clinically actionable stratification of uncommon MET fusions: a precision oncology framework.

BACKGROUND: MET fusions represent emerging therapeutic targets in solid tumors; however, functional interpretation of non-canonical variants remains poorly understood, posing a major challenge for precision oncology. METHODS: We conducted a multicenter, pan-cancer study analyzing 23,299 clinical samples using DNA-based next-generation sequencing (NGS) to profile MET fusions. Transcriptional validation was performed using RNA-based NGS on available samples. Preliminary clinical outcomes were assessed in four patients with advanced malignancies harboring uncommon MET fusions who received MET tyrosine kinase inhibitor therapy. RESULTS: We identified 116 MET fusions (incidence: 0.5%), with 55.2% (64/116) classified as uncommon fusions. These uncommon fusions were stratified into: Group A (5’-retained, n = 12), Group B (intergenic/exonic breakpoints, n = 19), Group C (rare partners, n = 23), and Group D (dual fusions, n = 10). RNA validation revealed an overall low transcriptional consistency of 43.8% (14/32) for uncommon fusions, versus 100% for canonical fusions (PTPRZ1::MET, CAPZA2::MET). Notably, most 5’-retained fusions were transcriptionally silent, while some intergenic fusions resolved into expressed canonical partners (e.g. PTPRZ1::MET). Therapeutically, all four MET inhibitor-treated patients achieved partial responses, including pediatric diffuse midline gliomas (DMG) (median OS: 11.2 months) and lung adenocarcinoma (median OS: 34 months), demonstrating preliminary clinical activity. CONCLUSIONS: uncommon MET fusions are heterogeneous at genomic and transcriptional levels. DNA-level findings often do not predict functional transcripts, underscoring the necessity of RNA-based confirmation for clinical interpretation. Despite low overall consistency, a subset retains therapeutic potential. We propose a refined diagnostic framework integrating DNA-based stratification and RNA validation to guide the management of MET-altered cancers in precision oncology workflows.

Humans↗
PubMed2025

A MGMT Enhancer Variant is Associated with Glioma Susceptibility and Progression.

The O6-methylguanine-DNA methyltransferase (MGMT) plays a significant role in the pathogenesis and progression of glioma. Numerous enhancer variants, including those within the MGMT gene region and adjacent gene regions, have been found to be associated with cancer development and progression. We investigated the significance of enhancer variants located in the intergenic spacer far from the MGMT gene in relation to glioma susceptibility and progression. We recruited 402 glioma patients and 654 controls for this investigation using Sequenom MassARRAY genotyping. We identified a significantly elevated risk of glioma among carriers with the rs11016629 TG genotype compared to those with the GG genotype (OR = 1.41, 95% CI 1.03-1.93; P = 0.034). Subgroup analyses revealed that rs11016629 was significantly associated with glioma risk in subjects with WHO grade IV tumor (OR = 1.59, 95% CI 1.07-2.38; P = 0.023) and high-grade glioma (OR = 1.57, 95% CI 1.11-2.21; P = 0.011). Patients who underwent gross total resection with TG/TT genotypes exhibited a 2.66-fold higher risk of disease progression than GG carriers (HR = 2.66, 95% CI 1.23-5.79; P = 0.014). The study demonstrates that a MGMT enhancer variant rs11016629 contributes to both glioma susceptibility and progression.

Humans↗
PubMed2026

Di-, tri-, and tetranucleotide frequencies covary with lifespan and genome size across protostome invertebrates.

Animal lifespans span orders of magnitude, yet how genome sequence covaries with lifespan remains poorly characterized outside vertebrates. Although promoter CpG density has been linked to vertebrate longevity due to its gene-regulatory function through DNA methylation, it is unclear whether such patterns are promoter- and CpG-specific, or if they reflect broader sequence evolution. We curated maximum lifespan estimates for 466 protostome species spanning eight phyla with available genome assemblies and quantified mono-, di-, tri-, and tetranucleotide composition across whole genomes, intergenic regions, and six gene-associated regions (two upstream regions, exons, introns, and two downstream regions) defined using Benchmarking Universal Single-Copy Orthologs. Dinucleotide observed/expected ratios showed significant associations with lifespan and genome size in different ways. Lifespan-associated motifs were most pronounced in gene-associated non-coding regions, especially in introns and downstream regions, whereas genome-size effects were strongest in whole-genome and intergenic sequence. Tri- and tetranucleotide observed/expected ratios broadly recapitulated this regional organization. In contrast, GC content was not associated with lifespan across regions, indicating that the observed signals are not explained by mononucleotide composition but instead by how those nucleotides are arranged into short sequence motifs. These results suggest that lifespan and genome size show distinct but overlapping associations with regional sequence composition across invertebrate species and that lifespan-associated motif evolution extends beyond vertebrate promoter methylation architectures.

CpG density↗