抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Chromatin Modifications and Their Function

DNA methylation is a crucial epigenetic modification of the genome that is involved in regulating many cellular processes. These include embryonic development, transcription, chromatin structure, X chromosome inactivation, genomic imprinting and chromosome stability. Consistent with these important roles, a growing number of human diseases have been found to be associated with aberrant DNA methylation. The study of these diseases has provided new and fundamental insights into the roles that DNA methylation and other epigenetic modifications have in development and normal cellular homeostasis.

/pdf/dna-methylation-and-human-disease-3351ezm3g8.pdf

Dna methylation and human disease

MicroRNAs (miRNAs) are small, endogenous RNAs that regulate gene expression in plants and animals. In plants, these approximately 21-nucleotide RNAs are processed from stem-loop regions of long primary transcripts by a Dicer-like enzyme and are loaded into silencing complexes, where they generally direct cleavage of complementary mRNAs. Although plant miRNAs have some conserved functions extending beyond development, the importance of miRNA-directed gene regulation during plant development is now particularly clear. Identified in plants less than four years ago, miRNAs are already known to play numerous crucial roles at each major stage of development-typically at the cores of gene regulatory networks, targeting genes that are themselves regulators, such as those encoding transcription factors and F-box proteins.

/pdf/micrornas-and-their-regulatory-roles-in-plants-11zqu0d6p0.pdf

MicroRNAs AND THEIR REGULATORY ROLES IN PLANTS

Double-stranded RNA (dsRNA) is an important regulator of gene expression in many eukaryotes. It triggers different types of gene silencing that are collectively referred to as RNA silencing or RNA interference. A key step in known silencing pathways is the processing of dsRNAs into short RNA duplexes of characteristic size and structure. These short dsRNAs guide RNA silencing by specific and distinct mechanisms. Many components of the RNA silencing machinery still need to be identified and characterized, but a more complete understanding of the process is imminent.

Mechanisms of gene silencing by double-stranded RNA

RNA interference (RNAi) is a widespread silencing mechanism that acts at both the posttranscriptional and transcriptional levels. Here, we describe the purification of an RNAi effector complex termed RITS (RNA-induced initiation of transcriptional gene silencing) that is required for heterochromatin assembly in fission yeast. The RITS complex contains Ago1 (the fission yeast Argonaute homolog), Chp1 (a heterochromatin-associated chromodomain protein), and Tas3 (a novel protein). In addition, the complex contains small RNAs that require the Dicer ribonuclease for their production. These small RNAs are homologous to centromeric repeats and are required for the localization of RITS to heterochromatic domains. The results suggest a mechanism for the role of the RNAi machinery and small RNAs in targeting of heterochromatin complexes and epigenetic gene silencing at specific chromosomal loci.

https://science.sciencemag.org/content/sci/303/5658/672.full.pdf

RNAi-Mediated Targeting of Heterochromatin by the RITS Complex

/pdf/heterochromatin-revisited-nat-rev-genet-1s49kjmsfl.pdf

Heterochromatin revisited. Nat Rev Genet

RNA interference is a conserved mechanism by which double-stranded RNA is processed into short interfering RNAs (siRNAs) that can trigger both post-transcriptional and transcriptional gene silencing. In fission yeast, the RNA-induced initiation of transcriptional gene silencing (RITS) complex contains Dicer-generated siRNAs and is required for heterochromatic silencing. Here we show that RITS components, including Argonaute protein, bind to all known heterochromatic loci. At the mating-type region, RITS is recruited to the centromere-homologous repeat cenH in a Dicer-dependent manner, whereas the spreading of RITS across the entire 20-kb silenced domain, as well as its subsequent maintenance, requires heterochromatin machinery including Swi6 and occurs even in the absence of Dicer. Furthermore, our analyses suggest that RNA interference machinery operates in cis as a stable component of heterochromatic domains with RITS tethered to silenced loci by methylation of histone H3 at Lys9. This tethering promotes the processing of transcripts and generation of additional siRNAs for heterochromatin maintenance.

/pdf/rits-acts-in-cis-to-promote-rna-interference-mediated-4o09esicmg.pdf

RITS acts in cis to promote RNA interference-mediated transcriptional and post-transcriptional silencing.

Gene-specific repression of transcription plays a central role in gene regulation. This is true for the spatial control of gene activity in development, during which boundaries of gene expression are often determined by the spatially restricted localization or activity of transcriptional repressors (Mannervik et al. 1999). It is also true for the control of gene expression by extracellular signals, in which genes are often maintained in an off state by repressor proteins until signal transduction alleviates the repression (e.g., Roose and Clevers 1999). One of the most useful ways of categorizing repressors is according to whether they mediate long-range or short-range repression (Gray and Levine 1996b). In longrange repression, a repressor makes a promoter resistant to the influence of all enhancers, even if those enhancers are located thousands of base pairs from the repressor binding site. This kind of repression is often referred to as silencing because an entire chromosomal locus is inactivated. In contrast, short-range repressors function in a less general manner. Rather than interfering with all transcription at a locus, they block the function of nearby DNA-bound activators while not interfering with more distantly bound activators. In this review, we discuss examples of both long-range and short-range repression, showing that long-range repression may often involve the assembly of a multiprotein complex termed a repressosome that is analogous in many ways to the enhanceosomes known to mediate activation. Furthermore, we discuss how both long-range and short-range repression may involve the recruitment of histone deacetylases to the template and discuss models that may allow these enzymes to mediate both types of repression. Finally, we consider the possibility that interactions between repressors and the basal machinery as well as between repressors and activators play roles in long-range and short-range repression.

/pdf/transcriptional-repression-the-long-and-the-short-of-it-59031y198k.pdf

Transcriptional repression: the long and the short of it

At the silent mating-type interval of fission yeast, the RNA interference (RNAi) machinery cooperates with cenH, a DNA element homologous to centromeric repeats, to initiate heterochromatin formation. However, in RNAi mutants, heterochromatin assembly can still occur at low efficiency. Here, we report that Atf1 and Pcr1, two ATF/CREB family proteins, act in a parallel mechanism to the RNAi pathway for heterochromatin nucleation. Deletion of atf1 or pcr1 alone has little effect on silencing at the mating-type region, but when combined with RNAi mutants, double mutants fail to nucleate heterochromatin assembly. Moreover, deletion of atf1 or pcr1 in combination with cenH deletion causes loss of silencing and heterochromatin formation. Furthermore, Atf1 and Pcr1 bind to the mating-type region and target histone H3 lysine-9 methylation and the Swi6 protein essential for heterochromatin assembly. These analyses link ATF/CREB family proteins, involved in cellular response to environmental stresses, to nucleation of constitutive heterochromatin.

https://science.sciencemag.org/content/sci/304/5679/1971.full.pdf

Songtao Jia

Papers

RNAi-Mediated Targeting of Heterochromatin by the RITS Complex

Heterochromatin revisited. Nat Rev Genet

RITS acts in cis to promote RNA interference-mediated transcriptional and post-transcriptional silencing.

Transcriptional repression: the long and the short of it

RNAi-independent heterochromatin nucleation by the stress-activated ATF/CREB family proteins.