Articles in 2016

In meiosis, double-strand breaks (DSBs) are induced to initiate chromosome pairing and synapsis. Stanzione et al. identify IHO1 as a protein recruited by HORMAD1 to unsynapsed chromosome axes and required for DSB formation.

De novo generation of haematopoietic stem cells from different human pluripotent stem cell sources remains a high priority for haematology and regenerative medicine. At present, efficient derivation of functional haematopoietic stem cells with the capability for definitive in vivo engraftment and multi-lineage potential remains challenging. Here, we discuss recent progress and strategies to overcome obstacles that have thwarted past efforts. In addition, we review promising advances in the generation of mature blood lineages and the potential of induced pluripotent stem cells.

Festuccia et al. show that the pluripotency regulator Esrrb is retained on mitotic chromosomes, both in embryonic stem cells and during early embryogenesis, and epigenetically marks key regulatory regions during mitosis.

Bass et al. and Haahr et al. now identify ETAA1 as a critical replication stress response factor that interacts with DNA damage response proteins and activates ATR to maintain genomic stability.

Muthuswamy et al. report that in macrophages SCRIB interacts with the NADPH oxidase complex to promote the production of reactive oxygen species needed to kill bacteria. Conversely, loss of SCRIB promotes M1 macrophage polarization and inflammation.

Lysosomes are digestive organelles of the endocytic and autophagic pathways. Increasing lysosome enzyme activities could help to clear pathological cellular waste. A recent study shows that lysosomal digestive functions can be promoted in isolated cells and mice by pharmacologically stimulating the autophagy- and lysosome-regulating transcription factors TFEB and ZKSCAN3 through previously unrecognized mTORC1-independent pathways acting via PKC.

Limited perfusion of solid tumours produces a nutrient-deprived tumour core microenvironment. Low glutamine levels in the tumour core are now shown to lead to reduced levels of α-ketoglutarate and decreased histone demethylase activity, thereby promoting a less differentiated and more therapy-resistant state of the tumour cells.

Kodo et al. show that patient-specific iPSC-derived cardiomyocytes recapitulate the proliferative defects associated with the disease, which are a result of TBX20 mutations and abnormal TGF-β signalling.

Johnson et al. report that loss of leukaemia inhibitory factor receptor (LIFR) signalling reduces the expression of genes associated with dormancy in metastatic breast cancer cells, and promotes bone marrow colonization and osteoclastogenesis.

Using a chemical screening approach, Yang and colleagues identify PKC as a regulator of lysosome biogenesis, which controls the subcellular localization of TFEB and ZKSCAN3 through parallel signalling pathways and independently of mTORC1.

Microtubules can self-repair in vitro in response to stress. Théry and colleagues now show that such repair can occur in cells, as free tubulin dimers can be incorporated into a damaged microtubule lattice to promote rescue events.

Pan et al. find that regional glutamine deficiency in melanoma tumours induces tumour cell dedifferentiation and confers therapeutic resistance through histone methylation changes.

Guesdon et al. characterize the microtubule-end-binding region of EB1 using cryo-electron tomography, providing insights into the mechanism of this interaction and the architectural changes in the GTP-cap region during microtubule growth.

Using a chimaeric integrin α₅ (where the tail is replaced by that of α₂), Yun et al. show that in endothelial cells, integrin α₅ interacts with the cAMP-specific phosphodiesterase PDE4D5 to reduce cAMP levels and inflammation both in vitro and in vivo.

While the beneficial versus detrimental implications of the senescence-associated secretome remain an issue of debate, time-resolved analyses of its composition, regulatory mechanisms and functional consequences have been largely missing. The dynamic activity of NOTCH is now shown to direct two distinct senescence phenotypes, by first promoting a pro-senescent TGF-β1-dependent secretome, followed by a second wave of pro-inflammatory, senescence-clearing cytokines.

Extracellular vesicles, such as exosomes, are important effectors in the formation of tumour-fostering niches. Pigmented melanosomes are now shown to have a relevant role in establishing a tumour niche in primary melanoma by reprogramming dermal fibroblasts into cancer-associated fibroblasts through the transfer of miR-211.

Kim et al. demonstrate that sex hormones induce Mib1 expression in myofibres during puberty, initiating the conversion of cycling juvenile satellite cells into adult quiescent satellite cells.

Frede et al. use a chemical carcinogenesis model and lineage tracing to show that oesophageal tumour growth is driven by a single proliferating cancer cell population, suggesting the absence of a hierarchy of proliferating cells in this cancer type.

Dror et al. report that melanoma-derived melanosomes carry miRNAs that induce primary fibroblast reprogramming into cancer-associated fibroblasts, and also induce the formation of a pro-tumorigenic niche.