Research Highlights in 2012

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.

The LKB1 tumor suppressor encodes a serine-threonine kinase whose substrates control cell metabolism, polarity, and motility. LKB1 is a major mediator of the cellular response to energy stress via activation of the master regulator of energy homeostasis, AMPK. While mutational inactivation of LKB1 promotes the development of many types of epithelial cancer, a recent report in Nature by Jeon et al. demonstrates that the LKB1-AMPK pathway can also have an unexpected positive role in tumorigenesis, acting to maintain metabolic homeostasis and attenuate oxidative stress thereby supporting the survival of cancer cells.

The inside-out signaling of integrins regulates the ligand-binding affinity of the cell surface receptors in response to changes in the environment for cell survival. The specific binding to the cytoplasmic tail of integrin's β subunit by the intracellular protein talin is the key step of inside-out signaling. A “pull-push” mechanism has been proposed to explain how the PIP2-enriched membrane disrupts the dual auto-inhibition of the N-terminal talin-FERM domain by the C-terminal talin-rod domain such that activated talin-FERM can reach the β-tail for integrin activation.

The potentially life-threatening adverse reactions to Abavacir (ABC), a nucleoside analog reverse transcriptase inhibitor for the treatment of HIV infection, have been known for several years to be limited to individuals expressing the HLA-B^*57:01 gene. Why the ABC hypersensitivity syndrome is only seen in HLA-B^*57:01-expressing subjects and what the precise mechanisms underlying this intolerance are remain however controversial. A series of recent studies, particularly a study by Illing et al. recently published in Nature, now answer some of these questions and offer new opportunities to better understand autoimmune disorders and prevent adverse reactions to other drugs.

Proper control of intercellular communication through the Wnt signaling pathway is of critical importance for many aspects of biology, including head formation during vertebrate embryogenesis. A recent Cell paper describes the discovery of a novel protein, TIKI, which controls head size through a surprising new mechanism of Wnt antagonism.

The term “lineage reprogramming” is typically used to describe the conversion of one differentiated somatic cell type into another without transit through a pluripotent intermediate. Two recent reports in Nature demonstrate that such a conversion can be achieved in the heart in situ, and suggest a novel, regenerative approach for the development of cardiac therapeutics.

Cap-dependent translation is initiated by the binding of eIF4E to the cap structure at the 5′ end of mRNAs. During hypoxic stress, global translation decreases because eIF4E is inactivated. In a recent article in Nature, Lee and colleagues show that residual hypoxic translation is maintained by a specialized isoform of eIF4E, which binds to target mRNAs in complex with a hypoxia-induced RNP.

One of the two X chromosomes in cells of female mammals is transcriptionally silenced in a process known as X chromosome inactivation (XCI). Initiation of XCI is regulated by the ubiquitin ligase Rnf12/RLIM, but the mechanisms by which Rnf12/RLIM mediates this process has been a mystery. A recent study by Gontan et al. shows that Rnf12/RLIM targets REX1, an inhibitor of XCI, for proteasomal degradation, providing an answer to this question.

Salicylic acid (SA) is widely recognized as a key player in plant immunity. While several proteins have been previously identified as the direct targets of SA, SA-mediated plant defense signaling mechanisms remain unclear. The Nature paper from Xinnian Dong's group demonstrates that the NPR1 paralogues NPR3 and NPR4 directly bind SA, and this binding modulates their interaction with NPR1 and thereby degradation of this key positive regulator of SA-mediated defense, shedding important new insight into the mechanism(s) of SA-mediated, NPR1-dependent plant defense signal transduction.

Secreted proteins play essential roles in every step of cancer metastasis, while the identities and functions of those that contribute to tissue-specific metastasis are largely uncharacterized. Two articles in Cell Research report the discovery and functional analyses of novel secreted proteins that are biologically and clinically relevant to bone metastasis. The combinatory approaches represented here, together with advances in related technology, will promise a better understanding of the cancer secretome.

Adipose tissue remodeling is a dynamic process during nutritional fluctuation that plays critical roles in metabolic homeostasis and insulin sensitivity. The process is highly regulated by many factors, including adipokines and cytokines that are locally released within fat pads. In a recent study published in Nature, Jonker and colleagues identified FGF1 as an important mediator that is selectively induced in fat cells by high-fat diet feeding and established the PPARγ-FGF1 axis as a critical pathway that regulates adipose tissue remodeling and ultimately systemic metabolic homeostasis.

The link between impaired autophagic flux (autophagus interruptus), damaged mitochondria, and myocardial inflammation has been further tightened with the recent paper by Oka and colleagues, in which failure to degrade mitochondrial DNA exacerbated myocardial inflammation in the context of pressure overload. Using mice with cardiac-specific deletion of the lysosomal DNase II that were subjected to aortic banding, Otsu's group showed that mitochondrial DNA accumulated in lysosomes and resulted in TLR9-dependent production of inflammatory cytokines.

Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disorder often considered to be the third most common muscular dystrophy. Deletions reducing the copy number of the D4Z4 repeat in the distal end of the 4q arm are the main genetic cause of the disease. The recently highlighted research has identified a transcriptional activatory long non-coding RNA involved in the disease that acts through the recruitment of ASH1L, a protein belonging to the Trithorax family.

During fasting, dephosphorylation-dependent activation of the CREB coactivator CRTC2 by glucagon is crucial for activation of the hepatic gluconeogenic program, but the molecular mechanism by which hormones regulate CRTC2 activation remains unclear. A recent report in Nature showed that PKA-dependent phosphorylation of the inositol-1,4,5-trisphosphate receptor (InsP3R) induces Ca²⁺ mobilization, leading to increase in the phosphatase activity of calcineurin and the subsequent dephosphorylation of CRTC2, thereby resulting in the induction of gluconeogenic gene expression. It also showed that insulin-dependent phosphorylation of InsP3R by Akt inhibits Ca²⁺ mobilization and CRTC2 dephosphorylation, resulting in the suppression of gluconeogenesis.

In a recent issue of Nature, Hao et al. report an unexpected link between the secreted stem cell factor/Wnt agonist R-spondin and Wnt receptors through the transmembrane ZNRF3 protein, a RING finger ubiquitin ligase. ZNRF3 acts to turn over Frizzled and LRP6 receptors. R-spondin binds to ZNRF3, in addition to transmembrane LGR4/5 receptors, to antagonize degradation of the Wnt receptors by ZNRF3, thereby resulting in increased Frizzled and LRP6 levels and a greater Wnt response.

Although overlooked for many years, alternative cleavage and polyadenylation (APA) is now emerging as a major mechanism of gene regulation. A recent study identifies poly(A)-binding protein nuclear 1 (PABPN1), a general factor of polyadenylation, as a suppressor of alternative poly(A) sites.