Scaffold/matrix attachment regions (S/MARs): relevance for disease and therapy.

There is increasing awareness that processes, such as development, aging and cancer, are governed, to a considerable extent, by epigenetic processes, such as DNA and histone modifications. The sites of these modifications in turn reflect their position and role in the nuclear architecture. Since epigenetic changes are easier to reverse than mutations, drugs that remove or add the chemical tags are at the forefront of research for the treatment of cancerous and inflammatory diseases. This review will use selected examples to develop a unified view that might assist the systematic development of novel therapeutic regimens.

Genomewide identification of nuclear matrix attachment regions: an analysis of methods.

High-throughput technologies now afford the opportunity to directly determine the distribution of MARs (matrix attachment regions) throughout a genome. The utility of cosmid and oligonucleotide platforms to identify human chromosome 16 MARs from preparations that employed LIS (lithium di-iodosalicylic acid) and NaCl extraction protocols was examined. The effectiveness of the platforms was then evaluated by Q-PCR (quantitative real-time PCR). Analysis revealed that caution must be exercised, since the representation of non-coding regions varies among platforms. Nevertheless, several interesting trends were revealed. We expect that these technologies will prove useful in systems approaches directed towards defining the role of MARs in various cell types and cellular processes.

Computational and in vitro analysis of destabilized DNA regions in the interferon gene cluster: potential of predicting functional gene domains.

Recent evidence adds support to a traditional concept according to which the eukaryotic nucleus is organized into functional domains by scaffold or matrix attachment regions (S/MARs). These regions have previously been predicted to have a high potential for stress-induced duplex destabilization (SIDD). Here we report the parallel results of binding (reassociation) and computational SIDD analyses for regions within the human interferon gene cluster on the short arm of chromosome 9 (9p22). To verify and further refine the biomathematical methods, we focus on a 10 kb region in the cluster with the pseudogene IFNWP18 and the interferon alpha genes IFNA10 and IFNA7. In a series of S/MAR binding assays, we investigate the promoter and termination regions and additional attachment sequences that were detected in the SIDD profile. The promoters of the IFNA10 and the IFNA7 genes have a moderate approximately 20% binding affinity to the nuclear matrix; the termination sequences show stronger association (70-80%) under our standardized conditions. No comparable destabilized elements were detected flanking the IFNWP18 pseudogene, suggesting that selective pressure acts on the physicochemical properties detected here. In extended, noncoding regions a striking periodicity is found of rather restricted SIDD minima with scaffold binding potential. By various criteria, the underlying sequences represent a new class of S/MARs, thought to be involved in a higher level organization of the genome. Together, these data emphasize the relevance of SIDD calculations as a valid approach for the localization of structural, regulatory, and coding regions in the eukaryotic genome.