Reversible transitions between noradrenergic and mesenchymal tumor identities define cell plasticity in neuroblastoma

Noradrenergic and mesenchymal identities have been characterized in neuroblastoma cell lines according to their epigenetic landscapes and core regulatory circuitries. However, their relationship and relative contribution in patient tumors remain poorly defined. We now document spontaneous and reversible plasticity between the two identities, associated with epigenetic reprogramming, in several neuroblastoma models. Interestingly, xenografts with cells from each identity eventually harbor a noradrenergic phenotype suggesting that the microenvironment provides a powerful pressure towards this phenotype. Accordingly, such a noradrenergic cell identity is systematically observed in single-cell RNA-seq of 18 tumor biopsies and 15 PDX models. Yet, a subpopulation of these noradrenergic tumor cells presents with mesenchymal features that are shared with plasticity models, indicating that the plasticity described in these models has relevance in neuroblastoma patients. This work therefore emphasizes that intrinsic plasticity properties of neuroblastoma cells are dependent upon external cues of the environment to drive cell identity

The Sex-Specific Impact of Meiotic Recombination on Nucleotide Composition

Meiotic recombination is an important evolutionary force shaping the nucleotide landscape of genomes. For most vertebrates, the frequency of recombination varies slightly or considerably between the sexes (heterochiasmy). In humans, male, rather than female, recombination rate has been found to be more highly correlated with the guanine and cytosine (GC) content across the genome. In the present study, we review the results in human and extend the examination of the evolutionary impact of heterochiasmy beyond primates to include four additional eutherian mammals (mouse, dog, pig, and sheep), a metatherian mammal (opossum), and a bird (chicken). Specifically, we compared sex-specific recombination rates (RRs) with nucleotide substitution patterns evaluated in transposable elements. Our results, based on a comparative approach, reveal a great diversity in the relationship between heterochiasmy and nucleotide composition. We find that the stronger male impact on this relationship is a conserved feature of human, mouse, dog, and sheep. In contrast, variation in genomic GC content in pig and opossum is more strongly correlated with female, rather than male, RR. Moreover, we show that the sex-differential impact of recombination is mainly driven by the chromosomal localization of recombination events. Independent of sex, the higher the RR in a genomic region and the longer this recombination activity is conserved in time, the stronger the bias in nucleotide substitution pattern, through such mechanisms as biased gene conversion. Over time, this bias will increase the local GC content of the region

Modeling Neurodegeneration in Zebrafish

The zebrafish, Danio rerio, has been established as an excellent vertebrate model for the study of developmental biology and gene function. It also has proven to be a valuable model to study human diseases. Here, we reviewed recent publications using zebrafish to study the pathology of human neurodegenerative diseases including Parkinson’s, Huntington’s, and Alzheimer’s. These studies indicate that zebrafish genes and their human homologues have conserved functions with respect to the etiology of neurodegenerative diseases. The characteristics of the zebrafish and the experimental approaches to which it is amenable make this species a useful complement to other animal models for the study of pathologic mechanisms of neurodegenerative diseases and for the screening of compounds with therapeutic potential