News & Comment

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.

In a recent landmark paper, the Huntington's disease (HD) iPSC Consortium reports on the establishment and characterization of a panel of iPSC lines from HD patients, and more importantly, the successful modeling of HD in vitro. In the same issue of Cell Stem Cell, An et al. reports on the successful targeted gene correction of HD in human iPSCs. Both advances are exciting, provide new resources for current and future HD research, and uncover new challenges to better understand and, most importantly, treat this devastating disease in the near future.

In zygotes, a global loss of DNA methylation occurs selectively in the paternal pronucleus before the first cell division, concomitantly with the appearance of modified forms of 5-methylcytosine. The adjacent maternal pronucleus and certain paternally-imprinted loci are protected from this process. Nakamura et al. recently clarified the molecular mechanism involved: PGC7/Stella/Dppa3 binds to dimethylated histone 3 lysine 9 (H3K9me2), thereby blocking the activity of the Tet3 methylcytosine oxidase in the maternal genome as well as at certain imprinted loci in the paternal genome.

Two recent papers identify KRAS activation as a mechanism of acquired resistance to EGFR blockade in colorectal cancer. In doing so, they suggest that resistance to single-agent EGFR blockade will be unavoidable because these alterations exist as latent subclones within the tumor even prior to the initiation of therapy.

Sirtuins are NAD-dependent deacetylases that are conserved from yeast to mammals. A new report sheds light on the function of SIRT7, the least understood member of the Sirtuin family by identifying its locus-specific H3K18 deacetylase activity, and linking it to maintenance of cellular transformation in malignancies.

The laboratories of Galina Petukhova and R Daniel Camerini-Otero have achieved significant technical advances in determining the genome-wide sites of DNA double-strand breaks (DSBs) where the process of genetic exchange between chromatids during meiosis begins. Applying the new approaches to male meiosis in mice, their experimental results considerably increase our insights into the nature and regulation of these processes.