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At least 703 records · Page 39Linked to original sources
PubMed2004

Insertion of retroviral vectors in NOD/SCID repopulating human peripheral blood progenitor cells occurs preferentially in the vicinity of transcription start regions and in introns.

Reports on insertional "genotoxicity" in patients have created intense interest in characterizing retroviral vector integrations on the genomic level. The retroviral vector SF91m3 was used for transduction of human peripheral blood progenitor cells (PBPC). These PBPC were transplanted into nonobese diabetic/severe combined immunodeficient mice. A total of 186 retroviral vector integration sites were isolated by ligation-mediated PCR from chimeric mouse bone marrow of five PBPC donors, sequenced, and blasted against the human genome. Preferred integration near the transcription start regions, within CpG islands, and within Alu regions was observed. Detailed analysis of targeted RefSeq genes showed a favored integration within the first intron. Integrations were most common in genes coding for signaling proteins, transcription factors, and kinases. In all genes targeted independently multiple times the respective orientation of the provirus within the gene was identical, indicating integration hot spot regions and similar steric determinants for integration sites. Possible explanations for these findings could be nonrandom vector integration, clonal selection due to gene expression interference, or engraftment issues related to gene insertion in signaling and cell cycle genes. The low frequency of integrations in exons may be reassuring as to the safety of retroviral gene therapy with normal human PBPC.

Alu Elements↗
PubMed1999

The specific endoribonuclease activity of small nuclear and cytoplasmic alpha-RNPs.

For the first time small nuclear ribonucleoprotein particles (alpha-RNP) tightly bound to chromatin as well as cytoplasmic alpha-RNP are shown to possess strong and regulated endonuclease activity specific for mRNAs and hnRNAs. The enzymatic nature of this activity is confirmed, and the optimal conditions detected. This RNase activity is controlled by the action of a differentiating stimulus, dimethylsulfoxide, in human K562 cells. Small alpha-RNP involvement in the coordinated control of stability of pre-messenger RNA and messenger RNA molecules is suggested.

Alu Elements↗
PubMed2001

Molecular description of three macro-deletions and an Alu-Alu recombination-mediated duplication in the HPRT gene in four patients with Lesch-Nyhan disease.

Mutations in the HPRT gene cause a spectrum of diseases that ranges from hyperuricemia alone to hyperuricemia with profound neurological and behavioral dysfunction. The extreme phenotype is termed Lesch-Nyhan syndrome. In 271 cases in which the germinal HPRT mutation has been characterized, 218 different mutations have been found. Of these, 34 (13%) are large- (macro-) deletions of one exon or greater and four (2%) are partial gene duplications. The deletion breakpoint junctions have been defined for only three of the 34 macro-deletions. The molecular basis of two of the four duplications has been defined. We report here the breakpoint junctions for three new deletion mutations, encompassing exons 4-8 (20033bp), exons 4 and 5 (13307bp) and exons 5 and 6 (9454bp), respectively. The deletion breakpoints were defined by a combination of long polymerase chain reaction (PCR) amplifications, and conventional PCR and DNA sequencing. All three deletions are the result of non-homologous recombinations. A fourth mutation, a duplication of exons 2 and 3, is the result of an Alu-mediated homologous recombination between identical 19bp sequences in introns 3 and 1. In toto, two of three germinal HPRT duplication mutations appear to have been caused by Alu-mediated homologous recombination, while only one of six deletion mutations appears to have resulted from this type of recombination mechanism. The other five deletion mutations resulted from non-homologous recombination. With this admittedly limited number of characterized macro-mutations, Alu-mediated unequal homologous recombinations account for at least 8% (3 of 38) of the macro-alterations and 1% (3 of 271) of the total HPRT germinal mutations.

Alu Elements↗
PubMed1999

Control of genes by mammalian retroposons.

Available data on possible genetic impacts of mammalian retroposons are reviewed. Most important is the growing number of established examples showing the involvement of retroposons in modulation of expression of protein-coding genes transcribed by RNA polymerase II (Pol II). Retroposons contain conserved blocks of nucleotide sequence for binding of some important Pol II transcription factors as well as sequences involved in regulation of stability of mRNA. Moreover, these mobile genes provide short regions of sequence homology for illegitimate recombinations, leading to diverse genome rearrangements during evolution. Therefore, mammalian retroposons representing a significant fraction of noncoding DNA cannot be considered at present as junk DNA but as important genetic symbionts driving the evolution of regulatory networks controlling gene expression.

Alu Elements↗
PubMed2003

Identification of human cells in brain xenografts and in neural co-cultures of rat by in situ hybridisation with Alu probe.

Transplantation of human cells into animal models of neurodegenerative disorders is an important scientific application to analyse the survival and developmental capacity of grafted human cells under in vivo conditions. It is critical, therefore, to have a reliable method to distinguish between human and animal cells. In the present study, we describe a combined in situ hybridisation and immunocytochemistry method for the identification of human cells in cultured rat brain cells and xenografts. The specific Alu probe we utilised, which corresponds to the consensus sequence of human Alu repeats was evaluated by southern blot hybridisation of zoo blot and by in situ hybridisation of primary and neoplastic cells from man, rat, mouse, and hamster. This method allows a definite identification of human cells in neural xenografts and, in combination with additional in situ techniques, a further detection of grafted cells.

Alu Elements↗
PubMed2000

Beyond danger: unmethylated CpG dinucleotides and the immunopathogenesis of disease.

Oligonucleotide sequences containing unmethylated cytidine phosphate guanosine (CpG) motifs are known to have significant immunostimulatory properties. Because of these immunostimulatory effects, unmethylated CpG oligonucleotides are thought to act as 'danger signals' that produce a favorable immune response by alerting the host to the presence of invading organisms or abnormal cells. In contrast to this concept, we review the evidence that unmethylated CpG sequences derived either from microbial agents or from endogenous CpG-rich Alu motifs promote disease progression by inducing an aberrant or autoreactive immune response. Recognition of the negative effect of unmethylated CpG dinucleotides should lead to more effective immune strategies to combat infectious, inflammatory, autoimmune and malignant diseases.

Alu Elements↗
PubMed2000

The expression frequency of common fragile sites and genetic predisposition to colon cancer.

The expression frequency of common fragile sites induced by aphidicolin (Apc), bromodeoxyuridine (BrdU), and caffeine was evaluated on prometaphase chromosomes obtained from the peripheral blood lymphocytes of 32 patients with colon cancer, 30 of their clinically healthy family members and 30 age-matched normal controls. The proportion of damaged cells (P < 0.001), the mean number of chromosomal aberrations and the expression frequencies of fragile sites were significantly higher in the patient and relative groups compared to the control group. Our findings show an increased genetic instability in patients with colon cancer and their first-degree relatives. In addition, common fragile sites can be used as a suitable marker for determining genetic predisposition to cancer.

Adenocarcinoma↗
PubMed2001

An Alu cassette in the human epithelial sodium channel.

Here, we report the presence of two splice variants of the human epithelial sodium channel alpha subunit (h alpha ENaC) containing Alu cassette, namely h alpha ENaC+22 and h alpha ENaC+Alu, in various tissues. Functional expression of these splice variants with hENaC beta and gamma subunits produced loss-of-channel activity in the Xenopus oocyte expression system. Interestingly, coexpression of h alpha ENaC+22 or h alpha ENaC+Alu, respectively, with wild type hENaC alpha, beta, and gamma subunits enhanced the expression of amiloride-sensitive current in oocytes. The presence of Alu sequences in the 3'-untranslated region of h gamma ENaC was also identified.

Alternative Splicing↗
PubMed2002

Growth and decline of introns.

To gauge the processes that might direct the length of introns, I studied the balance of indels (insertions or deletions, determined using Alu and LINE1 retroposon repeats) and the density of these repeats in the introns of the human genome. The indel balance is biased in favour of deletions and correlated with the divergence of repeats. At fixed repeat divergence, the indel bias correlated with the intron size: the shorter the intron, the more deletions were favoured over insertions. This correlation with the intron size was stronger than with the gene-wide or isochore-wide parameters. The density of repeats (the number of repeats in a unit of intron length) correlated positively with the intron size. Thus, quite different mechanisms, the indel bias and the integration and/or persistence of retroposons, act in the same direction in regards to intron size, which suggests selection for the size of individual introns.

Alu Elements↗
PubMed2001

The peopling of the Canary Islands: a CD4/Alu microsatellite haplotype perspective.

A new CD4 microsatellite allele with three TTTTC complete repetitions, previously described only in hominoids, has been found in this screening. The number of haplotypes and heterozygosities in the Canary Islands (15 and 0.746+/-0.007) is more similar to Iberian (14 and 0.748+/-0.015) than to North African (18 and 0.827+/-0.009) values. However, in some islands, with less European migratory impact, haplotypes with major African assignation (90[+] and 130[+]) reach frequencies similar to African populations. There is a significant negative correlation between geographic distances to Africa and insular heterozygosity values, which suggests a main aborigine colonization from East to West still detectable today.

Alleles↗
PubMed2001

Genome-wide chromatin remodeling modulates the Alu heat shock response.

During heat shock recovery in Hela cells, the level of Alu RNA transiently increases with kinetics that approximately parallel the transient expression of heat shock protein mRNAs. Coincidentally, there is a transient increase in the accessibility of Alu chromatin to restriction enzyme cleavage suggesting that an opening and re-closing of chromatin regulates the Alu stress response. Similar changes occur in alpha satellite and LINE1 chromatin showing that heat shock induces a genome-wide remodeling of chromatin structure which is independent of transcription. The increased accessibility of restriction sites within these repetitive sequences is inconsistent with a simple lengthening of the nucleosome linker region but instead suggests a scrambling of nucleosome positions. Chromatin structure and its dynamics account for many of the principal features of SINE transcriptional regulation potentially providing a functional rationale for the dispersion and high copy number of SINEs.

Alu Elements↗