PubMed · 11719231
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J F Brookfield. 2001-11-13. Selection on Alu sequences?. https://doi.org/10.1016/s0960-9822(01)00547-4
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Based on the contents of the database S/MARt DB, the most comprehensive data collection of scaffold/matrix-attached regions (S/MARs) publicly available thus far, we initiated a systematic evaluation of the stored data. By analyzing the 245 S/MAR sequences presently described in this database, we found that the S/MARs contained in this collection are generally AT-rich, with certain significant exceptions. Comparative analyses showed that most of the AT-rich motifs which were found to be enriched in S/MARs are also enriched in randomized S/MAR sequences of the same AT content. Some sequence patterns previously suggested to be characteristic for S/MARs were also investigated, among them potential binding sites for homeodomain transcription factors. Even though hexanucleotides containing the core motif of homeodomain factors were frequently observed in S/MARs, only a few potential binding sites for these factors were found enriched when compared with regulatory regions or exon sequences. All our analyses indicated that, on average, the observed frequency of motifs in S/MAR elements is largely influenced by the AT content. Our results can serve as a guideline for further improvements in the definition of S/MARs, which are now believed to constitute the functional coordinate system for genomic regulatory regions.
Altered expression of c-myc is implicated in pathogenesis and progression of many human cancers. Triple helix-forming oligonucleotides (TFOs) directed to a polypurine/polypyrimidine sequence in a critical regulatory region near the c-myc P2 promoter have been shown to inhibit c-myc transcription in vitro and in cells. However, these guanine-rich TFOs had moderate binding affinity and required high concentrations for activity. The 23 bp myc P2 sequence is split equally into AT- and GC-rich tracts. Gel mobility analysis of a series of short TFOs directed in parallel and anti-parallel orientation to the purine strand of each tract showed that only parallel CT and anti-parallel GT TFOs formed stable triplex on the AT- and GC-rich tracts, respectively. A novel full-length GTC TFO was designed to bind simultaneously in parallel and anti-parallel orientation to the polypurine strand. Gel-shift and footprinting assays showed that the new TFO formed a triple helix in physiological conditions with significantly higher affinity than an anti-parallel TFO. Protein-binding assays showed that 1 microM GTC TFO inhibited binding of nuclear transcription factors to the P2 promoter sequence. The novel TFO can be developed into a potent antigene agent, and its design strategy applied to similar genomic sequences, thus expanding the TFO repertoire.
5-Bromodeoxyuridine induces a senescence-like phenomenon in mammalian cells. This effect was dramatically potentiated by AT-binding ligands such as distamycin A, netropsin, and Hoechst 33258. The genes most remarkably affected by these ligands include the widely used senescence-associated genes and were located on or nearby Giemsa-dark bands of human chromosomes. We hypothesize that AT-rich scaffold/nuclear matrix attachment region sequences are involved in this phenomenon. In fact, upon substitution of thymine with 5-bromouracil, a rat S/MAR sequence reduced its degree of bending and became insensitive to cancellation of the bending by distamycin A. The S/MAR sequence containing 5-bromouracil also bound more tightly to nuclear scaffold proteins in vitro and this binding was not inhibited by distamycin A. Under the same conditions, the S/MAR sequence containing thymine easily dissociated from the nuclear scaffold proteins. Taken together, the synergistic induction of the genes may be explained not only by opening of condensed chromatin by distamycin A but also by increase in the binding of 5-bromouracil-containing S/MAR sequences to the nuclear scaffolds.