Integrative Role of 14-3-3ε in Sleep Regulation

Sleep is a crucial factor for health and survival in all animals. In this study, we found by proteomic analysis that some cancer related proteins were impacted by the circadian clock. The 14-3-3ε protein, expression of which is activated by the circadian transcription factor Clock, regulates adult sleep of Drosophila independent of circadian rhythm. Detailed analysis of the sleep regulatory mechanism shows that 14-3-3ε directly targets the Ultrabithorax (Ubx) gene to activate transcription of the pigment dispersing factor (PDF). The dopamine receptor (Dop1R1) and the octopamine receptor (Oamb), are also involved in the 14-3-3ε pathway, which in 14-3-3ε mutant flies causes increases in the dopR1 and OAMB, while downregulation of the DopR1 and Oamb can restore the sleep phenotype caused by the 14-3-3ε mutation. In conclusion, 14-3-3ε is necessary for sleep regulation in Drosophila.

Combined statistical modeling enables accurate mining of circadian transcription

Circadian-regulated genes are essential for tissue homeostasis and organismal function, and are therefore common targets of scrutiny. Detection of rhythmic genes using current analytical tools requires exhaustive sampling, a demand that is costly and raises ethical concerns, making it unfeasible in certain mammalian systems. Several non-parametric methods have been commonly used to analyze short-term (24 h) circadian data, such as JTK_cycle and MetaCycle. However, algorithm performance varies greatly depending on various biological and technical factors. Here, we present CircaN, an ad-hoc implementation of a non-linear mixed model for the identification of circadian genes in all types of omics data. Based on the variable but complementary results obtained through several biological and in silico datasets, we propose a combined approach of CircaN and non-parametric models to dramatically improve the number of circadian genes detected, without affecting accuracy. We also introduce an R package to make this approach available to the community.

Genomic instability is an early event driving chromatin reorganization and escape from oncogene-induced senescence

SUMMARYOncogene-induced senescence (OIS) is an inherent and important tumor suppressor mechanism. However, if not timely removed via immune surveillance, senescent cells will also present a detrimental side. Although this has mostly been attributed to the senescence-associated-secretory-phenotype (SASP) of these cells, we recently proposed that “escape” from the senescent state represents another unfavorable outcome. Here, we exploit genomic and functional data from a prototypical human epithelial cell model carrying an inducible CDC6 oncogene to identify an early-acquired recurrent chromosomal inversion, which harbors a locus encoding the circadian transcription factor BHLHE40. This inversion alone suffices for BHLHE40 activation upon CDC6 induction and for driving cell cycle re-entry and malignant transformation. In summary, we now provide strong evidence in support of genomic instability underlying “escape” from oncogene-induced senescence.HIGHLIGHTSOncogene driven error-prone repair produces early genetic lesions allowing escape from senescenceCells escaping oncogene-induced senescence display mutational signatures observed in cancer patientsA single recurrent inversion harboring a circadian TF gene suffices for bypassing oncogene-induced senescenceChromatin loop and compartment remodeling support the “escape” transcriptional program

Out of breath, out of time: interactions between HIF and circadian rhythms

Humans have internal circadian clocks that ensure that important physiological functions occur at specific times of the day. These molecular clocks are regulated at the genomic level and exist in most cells of the body. Multiple circadian resetting cues have been identified, including light, temperature, and food. Recently, oxygen has been identified as a resetting cue, and emerging science indicates that this occurs through interactions at the cellular level between the circadian transcription-translation feedback loop and the hypoxia-inducible pathway (hypoxia-inducible factor; subject of the 2019 Nobel Prize in Physiology or Medicine). This review will cover recently identified relationships between HIF and proteins of the circadian clock. Interactions between the circadian clock and hypoxia could have wide-reaching implications for human diseases, and understanding the molecular mechanisms regulating these overlapping pathways may open up new strategies for drug discovery.