肿瘤发生的表观遗传学:进展与临床意义

表观遗传(epigenetics)指所有不通过DNA序列改变就能影响基因表达(从而决定细胞乃至个体表型)的、可遗传的(即可伴随细胞分裂传递下去)调控方式,包括DNA甲基化、组蛋白修饰、染色质重塑、miRNA、朊病毒等。表观遗传调控在干细胞自我更新、定向分化、器官发育等生命过程中起着至关重要的作用:每一个多细胞生物个体都是由一个受精     

The epigenetics of Alzheimer's disease--additional considerations

The critical commentaries following our review of the epigenetics of Alzheimer's disease (AD) amplify a number of key points with respect to the role of 1-carbon metabolism, the phenomenon of allele-specific methylation, the potentially critical explanatory link provided by epigenetic mechanisms for genome-wide association and large-scale gene expression array studies, and new therapeutic approaches afforded by epigenetic manipulation in Alzheimer's disease.     

The last two millennias echo-catastrophes are the driving forces for the potential genetic advantage mechanisms in celiac disease

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.     

Epigenetic modifications induced by early enrichment are associated with changes in timing of induction of BDNF expression

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.     

Remembrance of things past retrieved from the Paramecium genome

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.     

Tetrahymena thermophila, a unicellular eukaryote with separate germline and somatic genomes

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.     

Involvement of DNA hypermethylation in down-regulation of the zinc transporter ZIP8 in cadmium-resistant metallothionein-null cells

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.