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71.
Aaron L 《Medical hypotheses》2011,77(5):773-776
Many human genes have adapted to the constant threat of exposure to changing environmental conditions. Balancing selection is the result of an initial stage of positive selection that favors the spread in a population of a new allele until selection opposes its fixation and balanced situation is established. It is suggested that the disadvantageous celiac patients survived the last two millennias echo-catastrophes by adapting to the extreme temperature changes and their consequences in Europe. Genetic selective diversity induced by changing environment, enabled the celiac population to survive. Such a genetic positive selection is represented by the HEF C282Y mutation of hemochromatosis, SH2B3 loci and the HLA celiac disease-associated repertoire, enabling the celiac to overcome iron deficiency anemia and micro pathogen richness, respectively. The increased incidence of those evolutionary events in the celiac patients is a recent phenomenon that occurred in the latest era of the modern human history. The present hypothesis can shed light on additional selective genetic adaptations, echo catastrophe-driven that are at the basis of autoimmune disease-affected population survival and current expansion. 相似文献
72.
During early postnatal phase, the environment deeply affects developmental trajectories through epigenetic mechanisms that control the levels of key molecules for brain function, such as neurotrophins. Indeed, it has been shown that adverse early experiences induce epigenetic modifications leading to decreased brain derived neurotrophic factor (BDNF) levels at adulthood. However, no data about the effects of enriching early experiences are available. Here we exploit the mouse Communal Nest (CN) paradigm in order to investigate the effects of a highly stimulating early social environment on BDNF epigenetic modifications and protein expression at adulthood. CN, which consists of a single nest where three mothers keep their pups together and share care-giving behavior until weaning, is characterized by high levels of maternal behavior and peer interactions. Our results show that CN leads to high levels of histone acetylation at the BDNF gene at adulthood, which is more permissive to expression. However, such epigenetic modification is associated to increased BDNF protein expression only 1 h after an environmental challenge and not at baseline or 3 h after the challenge, suggesting that the epigenetic modifications do not affect expression under steady-state conditions but allow a fast increase in BDNF levels following stimulation. The present findings corroborate the role of epigenetic modifications in mediating the effects of the early social environment on adult brain function and behavior. In addition, these show, for the first time, an association between an epigenetic modification and a change in the rapidity of induction of protein expression, expanding the knowledge on the mechanisms by which epigenetic changes modify brain function. 相似文献
73.
Sperling L 《Research in microbiology》2011,162(6):587-597
Paramecium and other ciliates are the only unicellular eukaryotes that separate germinal and somatic functions. A germline micronucleus transmits the genetic information to sexual progeny, while a somatic macronucleus expresses the genetic information during vegetative growth to determine the phenotype. At each sexual generation, a new macronucleus develops from the zygotic nucleus through programmed rearrangements of the germline genome. Paramecium tetraurelia somatic genome sequencing, reviewed here, has provided insight into the organization and evolution of the genome. A series of at least 3 whole genome duplications was detected in the Paramecium lineage and selective pressures that determine the fate of the gene duplicates analyzed. Variability in the somatic DNA was characterized and could be attributed to the genome rearrangement processes. Since, in Paramecium, alternative genome rearrangement patterns can be inherited across sexual generations by homology-dependent epigenetic mechanisms and can affect phenotype, I discuss the possibility that ciliate nuclear dimorphism buffers genetic variation hidden in the germline. 相似文献
74.
Tetrahymena thermophila is a ciliate - a unicellular eukaryote. Remarkably, every cell maintains differentiated germline and somatic genomes: one silent, the other expressed. Moreover, the two genomes undergo diverse processes, some as extreme as life and death, simultaneously in the same cytoplasm. Conserved eukaryotic mechanisms have been modified in ciliates to selectively deal with the two genomes. We describe research in several areas of Tetrahymena biology, including meiosis, amitosis, genetic assortment, selective nuclear pore transport, somatic RNAi-guided heterochromatin formation, DNA excision and programmed nuclear death by autophagy, which has enriched and broadened knowledge of those mechanisms. 相似文献
75.
76.
Hitomi Fujishiro Satomi Okugaki Saori Yasumitsu Shuichi Enomoto Seiichiro Himeno 《Toxicology and applied pharmacology》2009,241(2):101-125
The Zrt/Irt-related protein 8 (ZIP8) encoded by slc39a8 is now emerging as an important zinc transporter involved in cellular cadmium incorporation. We have previously shown that mRNA and protein levels of ZIP8 were decreased in cadmium-resistant metallothionein-null (A7) cells, leading to a decrease in cadmium accumulation. However, the mechanism by which ZIP8 expression is suppressed in these cells remains to be elucidated. In the present study, we investigated the possibility that epigenetic silencing of the slc39a8 gene by DNA hypermethylation is involved in the down-regulation of ZIP8 expression. A7 cells showed a higher mRNA level of DNA methyltransferase 3b than parental cells. Hypermethylation of the CpG island of the slc39a8 gene was detected in A7 cells. Treatment of A7 cells with 5-aza-deoxycytidine, an inhibitor of DNA methyltransferase, caused demethylation of the CpG island of the slc39a8 gene and enhancement of mRNA and protein levels of ZIP8. In response to the recovery of ZIP8 expression, A7 cells treated with 5-aza-deoxycytidine showed an increase in cadmium accumulation and consequently an increase in sensitivity to cadmium. These results suggest that epigenetic silencing of the slc39a8 gene by DNA hypermethylation plays an important role in the down-regulation of ZIP8 in cadmium-resistant metallothionein-null cells. 相似文献
77.
78.
J?rg D?tsch Christian Plank Kerstin Amann Julie Ingelfinger 《Journal of molecular medicine (Berlin, Germany)》2009,87(9):841-848
Large epidemiological studies suggest a clear relation between low birth weight and adverse renal outcomes evident as early
as during childhood. Such adverse outcomes may include glomerular disease, hypertension, and renal failure. Data from autopsy
material and from experimental models suggest that reduction in nephron number via diminished nephrogenesis may be a major
mechanism, and factors that lead to this reduction are incompletely elucidated. Other mechanisms appear to be renal (e.g.,
via the intrarenal renin–angiotensin–aldosterone system) and nonrenal (e.g. changes in endothelial function). It also appears
likely that the outcomes of fetal programming may be influenced postnatally, for example, by the amount of nutrients given
at critical times. 相似文献
79.
随着人类对肿瘤研究的日益深入,许多学者已经清楚地认识到,肿瘤的发生、发展不仅与细胞内基因突变、缺失等因核苷酸序列改变所导致的遗传调控紊乱有关,还与表观遗传调控异常有着密切的联系[1].所谓表观遗传,是指通过DNA甲基化、组蛋白乙酰化和甲基化、染色质构型变化等所导致的在基因表达水平的改变.它只影响基因的转录活性而不影响核苷酸序列的改变[2].其中,DNA甲基化作为常见的表观遗传学修饰模式,在哺乳动物基因表达调控中起着重要的作用.异常甲基化可导致癌基冈的活化、非必需重复序列的转录、抑癌基因及DNA修复基因的沉默等,并能以半保留的方式高保真地传递到子代细胞的基岗组中,最终引发肿瘤[1]. 相似文献
80.
Inhibition of histone deacetylation protects wildtype but not gelsolin-deficient mice from ischemic brain injury 总被引:1,自引:0,他引:1
Yildirim F Gertz K Kronenberg G Harms C Fink KB Meisel A Endres M 《Experimental neurology》2008,210(2):531-542
Acetylation/deactylation of histones is an important mechanism to regulate gene expression and chromatin remodeling. We have previously demonstrated that the HDAC inhibitor trichostatin A (TSA) protects cortical neurons from oxygen/glucose deprivation in vitro which is mediated--at least in part--via the up regulation of gelsolin expression. Here, we demonstrate that TSA treatment dose-dependently enhances histone acetylation in brains of wildtype mice as evidenced by immunoblots of total brain lysates and immunocytochemical staining. Along with increased histone acetylation dose-dependent up regulation of gelsolin protein was observed. Levels of filamentous actin were largely decreased by TSA pre-treatment in brain of wildtype but not gelsolin-deficient mice. When exposed to 1 h filamentous occlusion of the middle cerebral artery followed by reperfusion TSA pre-treated wildtype mice developed significantly smaller cerebral lesion volumes and tended to have improved neurological deficit scores compared to vehicle-treated mice. These protective effects could not be explained by apparent changes in physiological parameters. In contrast to wildtype mice, TSA pre-treatment did not protect gelsolin-deficient mice against MCAo/reperfusion suggesting that enhanced gelsolin expression is an important mechanism by which TSA protects against ischemic brain injury. Our results suggest that HDAC inhibitors such as TSA are a promising therapeutic strategy for reducing brain injury following cerebral ischemia. 相似文献