Research Highlights in 2012

The mammalian target of rapamycin (mTOR) protein kinase regulates a wide variety of cellular processes, including protein synthesis, yet the downstream translational program under the control of mTOR is poorly understood. Two recent studies by Hsieh et al. and Thoreen et al. now start to address this issue, and uncover a subset of genes translationally regulated by oncogenic mTOR signaling that may contribute to tumorigenesis.

Recent progress in the induced pluripotent stem cell (iPSC) field as well as the establishment of germline stem cell isolation and culture methodologies may provide an in vitro platform for the study of physiological and pathological human gamete development and open new avenues for cell replacement-based personalized treatment of infertility.

While many mechanisms have been proposed for microRNAs (miRNAs) function, most ultimately cause message degradation. A view has emerged that miRNAs silence gene expression by promoting the association of mRNA decay factors. Recent research results, however, suggest that in both zebrafish and fruit fly, translational inhibition is the initiating event of miRNA-mediated gene silencing.

A hallmark of the mammalian circadian timing system is synchronization of physiology and behavior, but when this synchronization is disturbed, chronic diseases such as metabolic syndrome and depression may develop. Three new studies show that nuclear receptors of the Rev-Erb family impact the circadian oscillator and its metabolic output and this can be modified with specific agonists. Hence, resynchronization of metabolic pathways by manipulation of the circadian oscillator using REV-ERB-specific agonists may represent a feasible therapeutic concept to target diseases rooted in a misaligned circadian system.

Intracellular NOD-like receptor (NLR) proteins are believed to play important roles in innate immune detection or immune regulation, but only a few NLR proteins are functionally defined. Recent intensive studies, largely in vitro, on NLRC5 reveal multiple and controversial roles of this NLR protein in signaling regulation of both innate and adaptive immune responses. Using independently generated Nlrc5-deficient mice, two studies have now established the physiological function of NLRC5 in transcriptional control of MHC class I molecules despite that its role in innate immune signaling remains to be further clarified.

CUL4B, a member of the cullin-RING ubiquitin ligase family, is frequently mutated in X-linked mental retardation (XLMR) patients. The study by Liu et al. showed that Cul4b plays an essential developmental role in the extra-embryonic tissues, while it is dispensable in the embryo proper during mouse embryogenesis. Viable Cul4b-null mice provide the first animal model to study neuronal and behavioral deficiencies seen in human CUL4B XLMR patients.

Macrophage migration inhibitory factor (MIF) is overexpressed in numerous tumors and has been correlated with the development of breast cancer, but the mechanism(s) have largely remained unknown. Suppression of autophagy has now been unraveled as a pivotal mechanism underlying MIF's role in breast cancer. Strikingly, the study demonstrates that MIF phenocopies the anti-autophagic effects of steroid receptor coactivator-3 (SRC-3), a known oncogene, which in turn drives MIF gene expression.

The BRAF inhibitors (BRAFi) induce anti-tumor responses in nearly 60% of patients with advanced ^V600BRAF-mutant melanomas but only 5% of patients with ^V600BRAF-mutant colorectal carcinomas. Earlier studies of how a subset of melanoma that initially responds to BRAFi but later acquires drug resistance pointed to the importance of receptor tyrosine kinases (RTKs) in drug escape. In a pair of recent reports, this RTK-mediated mechanism of acquired BRAFi resistance in melanoma is re-surfacing in the context of innate or primary BRAFi resistance in ^V600BRAF-mutant colorectal carcinomas, suggesting potential upfront therapeutic strategies to prevent BRAFi resistance.

Tissue-resident memory T cells (T_RM) are a new subset of memory cells that have been associated with enhanced protective immunity for their tissue of residence. A recent study by Jiang et al. sheds light on the migration behavior of T_RM in both infected and unifected skin, and their ability to provide protection against re-infection even within a previously uninfected skin tissue.

Recent advances in the generation of multipotent and expandable induced neural stem cells are exciting. They not only hold great promises for potential clinical applications but may also open up a new era for neural stem cell research in the near future.

A recent paper suggests that reduced exposure to germs results in the expansion of a cell type called natural killer T cells, which predisposes to colitis and asthma. Such a scenario could explain the Hygiene Hypothesis, which has been a puzzle for decades.

It is not clearly understood what happens at the interface between normal and transformed epithelial cells at the first step of carcinogenesis. A recent study reveals that the organized epithelial structure suppresses clonal expansion of transformed cells. Translocation from the epithelium or perturbation of intercellular adhesions may be required for transformed cells to evade the suppressive environments.

The cellular response to amino acids is controlled at the molecular level by TORC1. While many of the elements that participate in TORC1 signaling are known, we still have no clear idea how cells sense amino acids. Two recent studies found that leucyl-tRNA synthetase (LRS) is a leucine sensor for TORC1, in both yeast and mammalian cells.

Initial studies linking Sirtuins to longevity in yeast initiated what is now a rich vein of aging research that is full of promise and fraught with controversy. Missing was a demonstration that enhanced Sirtuin expression extends lifespan in mammals. Now Kanfi et al. provide the evidence but with an interesting plot twist – the lesser known SIRT6 is the longevity factor.

Humans can be divided into roughly three groups with distinct microbial communities in their gastro-intestinal tract. The microbiota contributes to metabolic activity in the gastro-intestinal tract of the host, but what mechanisms shape the composition of the gut microbiota, and how does a person's 'enterotype' affect metabolic processes in distant organs? Flavell and colleagues shed light on these questions by revealing an important role for inflammasomes in modulating the prevalence of colitogenic species, and by demonstrating that dysbiosis influences susceptibility to non-alcoholic steatohepatitis (NASH) and other manifestations of metabolic syndrome.

Aging is a key risk factor in neurodegenerative disease; however, little is known about cellular pathways that mediate age-associated degeneration of the brain. The Bonini lab has identified a conserved microRNA, miR-34, that plays a neuroprotective role in the aging Drosophila brain and suggests that it functions in temporal control of gene expression.

Efficient DNA damage sensing and repair is crucial to preserve genomic integrity and failure to detect or repair DNA breaks can cause mutations, contributing to the formation of tumors. One key protein required for mediating DNA repair is the tumor suppressor 53BP1. Recent studies now demonstrate the crucial role of K48-linked ubiquitination and protein degradation for 53BP1 recruitment at sites of DNA damage.

Hematopoietic stem cell transplantation remains the only curative therapy for certain genetic diseases of the hematopoietic system, including some inheritable deficiencies in red blood cells (RBC). Recent advances in induced pluripotent stem cells may open a new era for the cure of such severe genetic RBC diseases.

Tumor-associated mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes result in the loss of normal catalytic activity, the production of α-ketoglutarate (α-KG), and gain of a new activity, the production of an oncometabolite, R-2-hydroxylglutarate (R-2-HG). New evidence supports previous findings that R-2-HG acts as an antagonist of α-KG to competitively inhibit the activity of multiple α-KG-dependent dioxygenases, including both histones and DNA demethylases involved in epigenetic control of gene expression and cell differentiation, and also reveals an intriguing new facet of R-2-HG in tumorigenesis.

Histone modifications have previously been leveraged to map the locations of candidate enhancer and promoters in one dimensional genomic space. Chepelev et al. report the first Chromatin Interaction Analysis with Paired-End Tag (ChIA-PET) sequencing of a specific histone modification to systematically map long-range physical interactions among enhancer and promoters, yielding insights into the nature of these interactions.