Research Highlights in 2012

Transcriptionally silent sperm contains a variety of RNA fragments of both coding and non-coding transcripts. A recent article by Peng and colleagues reveals several new families of small RNAs enriched in sperm, which are derived from the same locus as tRNAs. The finding of these short fragments of tRNA in the sperm raises once again the question of the possible function(s) of such a miniaturized form of information carried by the spermatozoon.

In a recent paper published in Nature, Carrieri et al. have identified in mouse a neuron-specific antisense lncRNA transcribed in the opposite strand of Uchl1 mRNA. Antisense Uchl1 specifically promotes the translation of UCHL1 under rapamycin treatment. To do so, the lncRNA only requires a SINEB2 repeat and a small region with sequence complementarity to the regulated mRNA.

T lymphocytes express clonal receptors, called T cell receptors (TCRs), which specifically recognize antigens presented in combination with major histocompatibility molecules (MHC). To date, T cell antigens can be broadly categorized into two classes: peptides and lipids. A recent paper published in Nature by Kjer-Nielsen and colleagues reveals that a unique population of T lymphocytes expresses TCRs that recognize a completely new and unexpected class of antigens, vitamin metabolites.

Functional human cardiomyocytes hold great promise in cell transplantation-based therapy to treat many heart diseases. To meet this devastating and clinical need, researchers are infatuated with developing novel technologies and methodologies to efficiently generate cardiomyocytes through either stem cell differentiation or cell lineage transdifferentiation. Though exciting progress has been made, challenges remain to be addressed before the translation from bench side to bed side can be fulfilled.

An abundance of long non-coding RNA (lncRNA) present in most species from yeast to human are involved in transcriptional regulation, dosage compensation and imprinting. This underscores the importance of lncRNA as functional RNA despite the fact that they do not produce proteins. Two recent papers in Cell have demonstrated that transcription of the non-conserved lncRNAs, but not the RNAs themselves, is necessary to introduce co-transcriptional regulatory histone marks to regulate gene expression.

Repair of double-strand breaks by homologous recombination requires Repair of double-strand breaks by homologous recombination requires 5′-3′ resection of the DNA ends to create 3′ single-stranded DNA tails. While much progress has been made in identifying the proteins that directly participate in end resection, how this process occurs in the context of chromatin is not well understood. Two papers in Nature report that Fun30, a poorly characterized member of the Swi2/Snf2 family of chromatin remodelers, plays a role in end processing by facilitating the Exo1 and Sgs1-Dna2 resection pathways.

The significant correlation between disease aggressiveness and the gene and protein structures of the B-cell receptors (BCRs) expressed on chronic lymphocytic leukemia (CLL) cells, together with the evidence for chronic activation of the BCR pathway, have led to the hypothesis that this leukemia initiates and progresses by selecting normal B lymphocytes reactive with a restricted set of (auto)antigens. A study recently published in Nature identified a novel signal-initiating interaction between the third complementary determining region of the IG heavy chain variable domain (HCDR3) and an epitope in the second framework region (FR2) that appears to be unique to CLL B cells and that calls into question the need for classical antigen binding in the activation and expansion of the leukemic cells. These findings are discussed in the context of available information about the antigen reactivity of CLL B cells and its potential role in clonal survival and drive.

Human immunodeficiency virus type 1 (HIV-1) is the cause of AIDS. In recent years it has emerged that cellular interferon-stimulated genes (ISG), play important roles in cell-intrinsic restriction of HIV replication. A publication now describes a novel strategy employed by HIV-infected cells to restrict viral replication, which involves inhibition of viral mRNA translation by the ISG Schlafen 11.

Blood transfusion medicine requires a constant supply of platelets, which is now totally donor dependent. Recent advances in the generation of platelets in vitro through megakaryocytes (MKs) may provide protocols not only via pluripotent stem cells, including induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), but also via induced MKs (iMKs). For the first time, mouse and human fibroblasts are successfully transdifferentiated into iMKs by the introduction of three factors, p45NF-E2, Maf G, and Maf K.

The rapid mutation of RNA viruses allows for the acquisition of resistance to drugs directly targeting viral proteins. Therefore, a novel approach to the development of antivirals centers on targeting host factors critical to viral replication. A recent report has brought to light the potential for RNA viruses to also develop resistance against compounds targeting crucial host factors, suggesting that a combination of drugs with various targets may be necessary for preventing resistance.

Histone lysine demethylases are chromatin modifiers that play important roles in many pathological processes such as inflammation and cancer, making them potentially attractive drug targets. In a recent study, Kruidenier et al. provided proof of concept by identifying chemical matters that inhibit demethylation mediated by the two related histone H3 lysine 27 demethylases, KDM6A and 6B (UTX and JMJD3). The KDM6 inhibitor shows remarkable substrate selectivity and can inhibit transcription of a plethora of pro-inflammatory genes in cell culture by altering H3K27me3 level at some of the KDM6 target genes.

Dendrites exhibit self-avoidance, in which branches of the same neuron repel each other while overlapping with branches from neighboring neurons. A recent paper by Lefebvre and colleagues reveals that clustered protocadherins provide a basis for neuronal recognition during dendrite self-avoidance in vertebrates.

Interferon carries out its cellular effects, including its antiviral effects, by inducing the synthesis of many new proteins, amongst which is the IFIT (ISG56) family of proteins. The first crystal structure of an IFIT, reported by Yang et al., revealed several functional properties of the protein that may help us to better understand the biological functions of these proteins.

Efficient generation of functional human vascular endothelial cells and smooth muscle cells from pluripotent stem cells is an extensively studied topic and of great interest in the stem cell field. Though thought to be technically complex and difficult, substantial progress has been made towards this direction. Here we aim to summarize and discuss the most recent advances in this topic and their future perspective in research and clinic.

Interferon-gamma (IFN-γ) is crucial for immunity against different pathogens due to its broad effects on the multiple arms of the immune system. The regulation of IFN-γ immunity is of extensive interest to research as well as practical activity for drug discovery. New evidence supports previous findings that ubiquitin-like protein ISG15 acts as an extracellular cytokine and promotes IFN-γ production, providing intriguing insights of the importance of ISG15 into the control of human mycobacterial disease.

A recent paper gives the details on how specific small RNAs can program a protein to cleave an undesired piece of DNA and to provide immunity to a microbial cell.

Resistance to molecularly targeted therapies can result from genomic alterations in the tumor cells that reactivate oncogenic signaling. Less is known of tumor cell-extrinsic mechanisms of resistance to targeted therapies. Two recent studies have identified HGF as a soluble factor capable of mediating resistance to BRAF and HER2 inhibitors in a paracrine manner. These new findings suggest an important role for the tumor microenvironment in mediating resistance to molecularly targeted therapies.

Inflammasomes are multiprotein complexes that detect and respond to foreign and endogenous danger signals by activating caspase-1; active caspase-1, in turn, matures the pro-inflammatory IL-1β family cytokines by cleaving their pro-forms into the biologically active cytokines. The upstream mechanisms leading to inflammasome activation, in particular for the NRLP3 inflammasome, remain poorly understood. Lu and colleagues identify a new function of Protein Kinase R (PKR) for activating the NLRP1, NLRP3, NLRC4 and AIM2 inflammasomes, thus identifying a potential new target for treating inflammasome-mediated diseases.

Seminal studies in C. elegans contributed to our general understanding of programmed cell death conferred by apoptosis. A recent study unravelled a new form of cell death in the worm and provided insights into its regulation. Affected cells are shed from intact tissues, a modality of death likely to be conserved and relevant to cancer.

Endothelial cell adhesion to the extracellular matrix regulates migration and outgrowth of blood vessels during angiogenesis. Cell adhesion is mediated by integrins, which transduce signals from the extracellular environment into the cell and, in turn, are regulated by intracellular signaling molecules. In a paper recently published in Cell Research, Sandri et al. show that RIN2 connects three GTPases, R-Ras, Rab5 and Rac1, to promote endothelial cell adhesion through the regulation of integrin internalization and Rac1 activation.