The recruitment of chromatin modifiers by long noncoding RNAs: lessons from PRC2

Polycomb repressive complex-2 (PRC2) is a histone methyltransferase required for epigenetic silencing during development and cancer. Among chromatin modifying factors shown to be recruited and regulated by long noncoding RNAs (lncRNAs), PRC2 is one of the most studied. Mammalian PRC2 binds thousands of RNAs in vivo, and it is becoming a model system for the recruitment of chromatin modifying factors by RNA. Yet, well-defined PRC2-binding motifs within target RNAs have been elusive. From the protein side, PRC2 RNA-binding subunits contain no known RNA-binding domains, complicating functional studies. Here we provide a critical review of existing models for the recruitment of PRC2 to chromatin by RNAs. This discussion may also serve researchers who are studying the recruitment of other chromatin modifiers by lncRNAs.     

Small nucleolar RNAs: an abundant group of noncoding RNAs with diverse cellular functions

Small nucleolar RNAs represent an abundant, evolutionarily ancient group of noncoding RNAs which possess impressively diverse functions ranging from 2'-O-methylation and pseudouridylation of various classes of RNAs, through nucleolytic processing of rRNAs to the synthesis of telomeric DNA.     

Intronic noncoding RNAs and splicing

The gene organization of small nucleolar RNAs (snoRNAs) and microRNAs (miRNAs) varies within and among different organisms. This diversity is reflected in the maturation pathways of these small noncoding RNAs (ncRNAs). The presence of noncoding RNAs in introns has implications for the biogenesis of both mature small RNAs and host mRNA. The balance of the interactions between the processing or ribonucleoprotein assembly of intronic noncoding RNAs and the splicing process can regulate the levels of ncRNA and host mRNA. The processing of snoRNAs - both intronic and non-intronic - is well characterised in yeast, plants and animals and provides a basis for examining how intronic plant miRNAs are processed.     

Small noncoding RNAs controlling pathogenesis

Infectious diseases are a leading cause of mortality worldwide. A major challenge in achieving their eradication is a better understanding of bacterial pathogenesis processes. The recent discovery of small noncoding RNAs (sRNAs) as modulators of gene expression in response to environmental cues has brought a new insight into bacterial regulation. sRNAs coordinate complex networks of stress adaptation and virulence gene expression. sRNAs generally ensure such a regulation by pairing to mRNAs of effector and/or regulatory genes, or by binding to proteins. An updated view on bacterial models responsible for important infections illustrates the key role of sRNAs in the control of pathogenesis.     

Linc-ing Long noncoding RNAs and enhancer function

Enhancers are distal regulatory sequences that control gene expression in development. ?rom et?al. now report in Cell that some long noncoding RNAs have functional properties of enhancers. Known enhancers are also transcribed in cells in which they are active, suggesting that noncoding RNAs are integral to enhancer action.     

The copper-iron chronicles: The story of an intimate relationship

During the last decade there has been a surge of interest and activity in exploring the metabolic links between copper and iron. This review describes more than a century and a half of effort that has led to our current understanding. Particular attention is given to the early events since these are less well-known and appreciated. The landmark 1928 paper of Hart, Elvehjem and coworkers is generally given credit for the start of the copper/iron field, and specifically for the discovery of the role of copper in forming hemoglobin and in overcoming anemia. However, some credit for the ideas, observations, and experiments should be shared with several investigators of the previous century. These scientists and physicians were primarily motivated to find the causes and cures of chlorosis, a common form of anemia at the time. From his chemical determination of copper in red blood cells in 1848, Millon proposed a form of chlorosis due to copper deficiency. Likewise, Pécholier and Saint-Pierre, observing the robust health of young women working in copper factories, concluded that copper was helpful in preventing and overcoming chlorosis. The first direct experimental evidence for the theory was provided by the Italian physician Mendini, who in 1862 reported that supplementation of the diet with copper salts overcame chlorosis in young women. In the 1890s Cervello and his students in Italy, using semi-quantitative hematological measurements, confirmed the beneficial effects of copper on anemia both in patients and in animal models. There was nearly a 30-year period of inactivity, but the decade of the 1930s saw renewed interest and exciting developments in the field. The Elvehjem report of 1928 was quickly verified and extended by multiple laboratories on four continents. In the 1950s and 1960s Wintrobe and Cartwright and their colleagues localized, and started to systematically evaluate, the potential sites at which copper was likely to effect iron for hemoglobin synthesis, namely, intestinal absorption, release from storage, and cellular utilization during synthesis. The copper/iron connection also has a `flip-side', i.e., iron status can influence copper metabolism as first described by Warburg and Krebs in 1927. Thus, there are opportunities for feedback mechanisms at the cellular and physiological level that are not yet understood. The evaluation of these processes continues to this day, aided by modern molecular and genetic approaches. Studies of two copper proteins, ceruloplasmin and its recently discovered homologue hephaestin, have provided two molecular links connecting the pathways of copper and iron metabolism. The recent identification of other proteins of iron and copper metabolism, for example, copper ATPases and the membrane iron transporters DCT1/DMT1/Nramp2 and IREG1/MTP1/ferroportin1, are likely to fill crucial pathway gaps. The ongoing discovery of genes and gene mutations involved in the metabolism of copper and iron provides an important key to a deeper understanding of the connections between the pathways, and their physiological and pathological consequences. It is hoped that this historical review, by illuminating the complex paths that have led to the current state of knowledge, will contribute to our appreciation, our understanding, and perhaps our continued discovery of the connections between copper and iron.