Association and spreading of the Drosophila dosage compensation complex from a discrete roX1 chromatin entry site

In Drosophila, dosage compensation is controlled by the male-specific lethal (MSL) complex consisting of MSL proteins and roX RNAs. The MSL complex is specifically localized on the male X chromosome to increase its expression approximately 2-fold. We recently proposed a model for the targeted assembly of the MSL complex, in which initial binding occurs at approximately 35 dispersed chromatin entry sites, followed by spreading in cis into flanking regions. Here, we analyze one of the chromatin entry sites, the roX1 gene, to determine which sequences are sufficient to recruit the MSL complex. We found association and spreading of the MSL complex from roX1 transgenes in the absence of detectable roX1 RNA synthesis from the transgene. We mapped the recruitment activity to a 217 bp roX1 fragment that shows male-specific DNase hypersensitivity and can be preferentially cross-linked in vivo to the MSL complex. When inserted on autosomes, this small roX1 segment is sufficient to produce an ectopic chromatin entry site that can nucleate binding and spreading of the MSL complex hundreds of kilobases into neighboring regions.     

甲基苯丙胺成瘾的表观遗传学机制

苯丙胺类兴奋剂是全世界第二大滥用程度的药物,甲基苯丙胺作为苯胺类兴奋剂中的主要药物,是中国滥用的“头号毒品”。而现有的研究对甲基苯丙胺成瘾机制尚不清晰,且临床上对药物成瘾的治疗依然存在无药可医的局面。因此,发现新的成瘾机制和治疗策略尤为迫切。甲基苯丙胺成瘾与额前叶皮质（mPFC）、中脑腹侧被盖区（VTA）和伏隔核（NAc）中的多巴胺（DA）、谷氨酸（Glu）、去甲肾上腺素（NE）和血清素（SNRIS）等神经递质的异常释放有关。研究表明,这些神经递质受到表观遗传机制中组蛋白乙酰化、甲基化、泛素化和非编码RNA等调节,某些基因的表达在甲基苯丙胺的诱导过程中增强或被抑制,导致甲基苯丙胺依赖性产生。本文将针对表观遗传学对甲基苯丙胺成瘾机制的影响进行着重论述,以期推进临床开发甲基苯丙胺戒断药物的研究。     

Global histone post-translational modifications and cancer:Biomarkers for diagnosis,prognosis and treatment?

Global alterations in epigenetic landscape are now recognized as a hallmark of cancer. Epigenetic mechanismssuch as DNA methylation,histone modifications,nucleosome positioning and non-coding RNAs are proven to have strong association with cancer. In particular,covalent post-translational modifications of histone proteins are known to play an important role in chromatin remodeling and thereby in regulation of gene expression. Further,histone modifications have also been associated with different aspects of carcinogenesis and have been studied for their role in the better management of cancer patients. In this review,we will explore and discuss how histone modifications are involved in cancer diagnosis,prognosis and treatment.     

Epigenetic regulation in human melanoma: past and future

The development and progression of melanoma have been attributed to independent or combined genetic and epigenetic events. There has been remarkable progress in understanding melanoma pathogenesis in terms of genetic alterations. However, recent studies have revealed a complex involvement of epigenetic mechanisms in the regulation of gene expression, including methylation, chromatin modification and remodeling, and the diverse activities of non-coding RNAs. The roles of gene methylation and miRNAs have been relatively well studied in melanoma, but other studies have shown that changes in chromatin status and in the differential expression of long non-coding RNAs can lead to altered regulation of key genes. Taken together, they affect the functioning of signaling pathways that influence each other, intersect, and form networks in which local perturbations disturb the activity of the whole system. Here, we focus on how epigenetic events intertwine with these pathways and contribute to the molecular pathogenesis of melanoma.     

Non-coding RNAs, epigenetics and complexity

Several aspects of epigenetics are strongly linked to non-coding RNAs, especially small RNAs that can direct the cytosine methylation and histone modifications that are implicated in gene expression regulation in complex organisms. A fundamental characteristic of epigenetics is that the same genome can show alternative phenotypes, which are based in different epigenetic states. Some of the most studied complex epigenetic phenomena including transposon activity and silencing recently exemplified by piRNAs (piwi-interacting RNAs), position effect variegation, X-chromosome inactivation, parental imprinting, and paramutation have direct or indirect participation of an RNA component. Conceivably, most of the non-coding RNAs with no described function yet, are players in epigenetic mechanisms that are still not completely understood. In that regard, RNAs were recently implicated in new mechanisms of genetic information transfer in yeast, plants and mice. In this review article, the hypothesis that non-coding RNAs might be the main component of complex organisms acquired during evolution will be explored. The question of how evolutionary theories have been challenged by these molecules in association with epigenetic mechanisms will also be discussed here.     

MIWI2 targets RNAs transcribed from piRNA‐dependent regions to drive DNA methylation in mouse prospermatogonia

Argonaute/Piwi proteins can regulate gene expression via RNA degradation and translational regulation using small RNAs as guides. They also promote the establishment of suppressive epigenetic marks on repeat sequences in diverse organisms. In mice, the nuclear Piwi protein MIWI2 and Piwi‐interacting RNAs (piRNAs) are required for DNA methylation of retrotransposon sequences and some other sequences. However, its underlying molecular mechanisms remain unclear. Here, we show that piRNA‐dependent regions are transcribed at the stage when piRNA‐mediated DNA methylation takes place. MIWI2 specifically interacts with RNAs from these regions. In addition, we generated mice with deletion of a retrotransposon sequence either in a representative piRNA‐dependent region or in a piRNA cluster. Both deleted regions were required for the establishment of DNA methylation of the piRNA‐dependent region, indicating that piRNAs determine the target specificity of MIWI2‐mediated DNA methylation. Our results indicate that MIWI2 affects the chromatin state through base‐pairing between piRNAs and nascent RNAs, as observed in other organisms possessing small RNA‐mediated epigenetic regulation.