bims-ciryme 2020-04-05 papers

Neuroscience. 2020 Mar 25. pii: S0306-4522(20)30190-1. [Epub ahead of print]

Homer1a Undergoes Bimodal Transcriptional Regulation by CREB and the Circadian Clock.

Shogo Sato, Blynn G Bunney, Marquis P Vawter, William E Bunney, Paolo Sassone-Corsi.

Accumulating evidence points to a significant link between disrupted circadian rhythms and neuronal disfunctions, though the molecular mechanisms underlying this connection are virtually unexplored. The transcript Homer1a, an immediate early gene related to postsynaptic signaling, has been demonstrated to exhibit robust circadian oscillation in the brain, which supports the hypothesis that Homer1a mediates the communication between circadian inputs and neuronal activity. Here, we determined how the circadian clock is implicated in Homer1a gene regulation by using circadian clock Bmal1-mutant mice either in the presence or absence of stress stimulation. The Homer1 gene generates multiple transcripts, but only the short variant Homer1a responds to acute stress with sleep deprivation (SD) in mice. Chromatin immunoprecipitation assays revealed that both transcription factor CREB and the circadian clock component BMAL1 bind to the Homer1 promoter in mouse brain. Importantly, circadian Homer1a gene expression is unaltered in the absence of BMAL1, while its immediate early response to SD relies on BMAL1. Deletion of Bmal1 results in attenuated CREB activity in mouse brain, which appears to contribute to decreased expression of Homer1a in response to SD. In conclusion, Homer1a undergoes bimodal control by the circadian clock and CREB.

Keywords: BMAL1; CREB; Homer1a; circadian rhythms; sleep deprivation

DOI: https://doi.org/10.1016/j.neuroscience.2020.03.031

Curr Biol. 2020 Mar 26. pii: S0960-9822(20)30265-7. [Epub ahead of print]

Bacterial Infection Disrupts Clock Gene Expression to Attenuate Immune Responses.

María José de Leone, C Esteban Hernando, Andrés Romanowski, Daniel A Careno, Ana Faigón Soverna, Hequan Sun, Nicolás G Bologna, Martín Vázquez, Korbinian Schneeberger, Marcelo J Yanovsky.

The circadian clock modulates immune responses in plants and animals; however, it is unclear how host-pathogen interactions affect the clock. Here we analyzed clock function in Arabidopsis thaliana mutants with defective immune responses and found that enhanced disease susceptibility 4 (eds4) displays alterations in several circadian rhythms. Mapping by sequencing revealed that EDS4 encodes the ortholog of NUCLEOPORIN 205, a core component of the inner ring of the nuclear pore complex (NPC). Consistent with the idea that the NPC specifically modulates clock function, we found a strong enrichment in core clock genes, as well as an increased nuclear to total mRNA accumulation, among genes that were differentially expressed in eds4 mutants. Interestingly, infection with Pseudomonas syringae in wild-type (WT) plants downregulated the expression of several morning core clock genes as early as 1 h post-infection, including all members of the NIGHT LIGHT-INDUCIBLE AND CLOCK-REGULATED (LNK) gene family, and this effect was attenuated in eds4. Furthermore, lnk mutants were more susceptible than the WT to P. syringae infection. These results indicate that bacterial infection, acting in part through the NPC, alters core clock gene expression and/or mRNA accumulation in a way that favors bacterial growth and disease susceptibility.

Keywords: Enhanced Disease Susceptibility 4; LNK; NIGHT LIGHT-INDUCIBLE AND CLOCK-REGULATED; NPC; Nuclear Pore Complex; eds4, circadian clock; plant-pathogen interactions

DOI: https://doi.org/10.1016/j.cub.2020.02.058

Front Cell Infect Microbiol. 2020 ;10 96

Circadian Regulation of Immunity Through Epigenetic Mechanisms.

Ricardo Orozco-Solis, Lorena Aguilar-Arnal.

The circadian clock orchestrates daily rhythms in many physiological, behavioral and molecular processes, providing means to anticipate, and adapt to environmental changes. A specific role of the circadian clock is to coordinate functions of the immune system both at steady-state and in response to infectious threats. Hence, time-of-day dependent variables are found in the physiology of immune cells, host-parasite interactions, inflammatory processes, or adaptive immune responses. Interestingly, the molecular clock coordinates transcriptional-translational feedback loops which orchestrate daily oscillations in expression of many genes involved in cellular functions. This clock function is assisted by tightly controlled transitions in the chromatin fiber involving epigenetic mechanisms which determine how a when transcriptional oscillations occur. Immune cells are no exception, as they also present a functional clock dictating transcriptional rhythms. Hereby, the molecular clock and the chromatin regulators controlling rhythmicity represent a unique scaffold mediating the crosstalk between the circadian and the immune systems. Certain epigenetic regulators are shared between both systems and uncovering them and characterizing their dynamics can provide clues to design effective chronotherapeutic strategies for modulation of the immune system.

Keywords: chromatin; circadian rhythm; epigenetics; infection; transcriptional regulation

DOI: https://doi.org/10.3389/fcimb.2020.00096