The long term goals of the Human Cell Genetics Section are: i) to elucidate mechanisms by which determinants of higher order chromatin structure and associated epigenetic mechanisms regulate cell growth and survival; and ii) to relate such cellular control mechanisms to senescence and age-related disease in the intact organism. Of particular interest is the hypothesis that damage and remodeling of chromatin-based structures contribute to mammalian senescence, both at the cellular and organismal levels. One approach to detect such remodeling is a semi-random sampling of genome chromatin structure, DDChIP, a method similar in principle to differential display. This approach has revealed a general picture of the distribution of H4 acetylation states across the human genome in non-immortalized diploid fibroblasts. Regions characterized by highly acetylated or under-acetylated histones (>12 each from over 2000 loci sampled) were identified and selected for further analysis. One such underacetylated heterochromatin-like locus, located near the centromere on chromosome 14, was studied in detail and demonstrated to extend over 20 kb. This work, together with previous experiments mapping chromatin structure along the 7q subtelomeric region, provides a basis to proceed with extensive screens for age- and differentiation-related chromatin remodeling in human cells. Concurrently, studies were initiated to map chromatin structure along the mouse genome. Using androgenetic and pathenogenetic mouse fibroblasts, several imprinted loci were found to display differential histone H3 methylation at lysine position 9 (K9) on the amino-terminal tail. The K9 modification is believed to mark classic HP1-related heterochromatin. This work yields new information on the mechanism of imprinting, and likewise provides a basis for more extensive DDChIP screening studies. A separate subproject is designed to ascertain whether determinants of higher order chromatin structure can modulate differentiation, proliferative potential, and immortalization. As part of this work, overexpression of dominant negative HDAC forms (HDAC1 (H140A), HDAC2 (H141A), and HDAC3 (H134A)) has been investigated in multiple cell culture systems. Cell types tested included murine erythroleukemia (MEL) cells and rat neuronal stem cells, as well as mouse and human fibroblasts. Both accelerated differentiation and senescence could be demonstrated; interestingly, however, relative activities of the various mutant HDACs proved to be very cell type-specific.
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| Golikov, Vladislav; Logacheva, Irina; Bruk, Gennadi et al. (2004) Modelling of long-term behaviour of caesium and strontium radionuclides in the Arctic environment and human exposure. J Environ Radioact 74:159-69 |
| Prichep, L S; Gugino, L D; John, E R et al. (2004) The Patient State Index as an indicator of the level of hypnosis under general anaesthesia. Br J Anaesth 92:393-9 |
| Oughton, Deborah; Forsberg, Ellen-Marie; Bay, Ingrid et al. (2004) An ethical dimension to sustainable restoration and long-term management of contaminated areas. J Environ Radioact 74:171-83 |
| Bae, Nancy S; Swanson, Mark J; Vassilev, Alex et al. (2004) Human histone deacetylase SIRT2 interacts with the homeobox transcription factor HOXA10. J Biochem (Tokyo) 135:695-700 |
| Howard, B; van Herck, H; Guillen, J et al. (2004) Report of the FELASA Working Group on evaluation of quality systems for animal units. Lab Anim 38:103-18 |
| Russanova, Valya R; Hirai, Tazuko H; Howard, Bruce H (2004) Semirandom sampling to detect differentiation-related and age-related epigenome remodeling. J Gerontol A Biol Sci Med Sci 59:1221-33 |
| Russanova, Valya R; Hirai, Tazuko H; Tchernov, Andrei V et al. (2004) Mapping development-related and age-related chromatin remodeling by a high throughput ChIP-HPLC approach. J Gerontol A Biol Sci Med Sci 59:1234-43 |
| Reid, Malcolm S; Prichep, Leslie S; Ciplet, Debra et al. (2003) Quantitative electroencephalographic studies of cue-induced cocaine craving. Clin Electroencephalogr 34:110-23 |
| Yamagoe, Satoshi; Kanno, Tomohiko; Kanno, Yuka et al. (2003) Interaction of histone acetylases and deacetylases in vivo. Mol Cell Biol 23:1025-33 |
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