bims-ciryme 2024-09-08 papers

Issue of 2024‒09‒08
two papers selected by
Gabriela Da Silva Xavier, University of Birmingham

Eur J Neurosci. 2024 Aug 28.

Multi-omics correlates of insulin resistance and circadian parameters mapped directly from human serum.

Ngoc-Hien Du, Flore Sinturel, Nora Nowak, Pauline Gosselin, Camille Saini, Idris Guessous, François R Jornayvaz, Jacques Philippe, Guillaume Rey, Emmanouil T Dermitzakis, Renato Zenobi, Charna Dibner, Steven A Brown.

While it is generally known that metabolic disorders and circadian dysfunction are intertwined, how the two systems affect each other is not well understood, nor are the genetic factors that might exacerbate this pathological interaction. Blood chemistry is profoundly changed in metabolic disorders, and we have previously shown that serum factors change cellular clock properties. To investigate if circulating factors altered in metabolic disorders have circadian modifying effects, and whether these effects are of genetic origin, we measured circadian rhythms in U2OS cell in the presence of serum collected from diabetic, obese or control subjects. We observed that circadian period lengthening in U2OS cells was associated with serum chemistry that is characteristic of insulin resistance. Characterizing the genetic variants that altered circadian period length by genome-wide association analysis, we found that one of the top variants mapped to the E3 ubiquitin ligase MARCH1 involved in insulin sensitivity. Confirming our data, the serum circadian modifying variants were also enriched in type 2 diabetes and chronotype variants identified in the UK Biobank cohort. Finally, to identify serum factors that might be involved in period lengthening, we performed detailed metabolomics and found that the circadian modifying variants are particularly associated with branched chain amino acids, whose levels are known to correlate with diabetes and insulin resistance. Overall, our multi-omics data showed comprehensively that systemic factors serve as a path through which metabolic disorders influence circadian system, and these can be examined in human populations directly by simple cellular assays in common cultured cells.

Keywords: GWAS; circadian rhythms; insulin resistance; obesity and type 2 diabetes; serum metabolomics

DOI: https://doi.org/10.1111/ejn.16486

Nat Commun. 2024 Sep 03. 15(1): 7674

Two KaiABC systems control circadian oscillations in one cyanobacterium.

Christin Köbler, Nicolas M Schmelling, Anika Wiegard, Alice Pawlowski, Gopal K Pattanayak, Philipp Spät, Nina M Scheurer, Kim N Sebastian, Florian P Stirba, Lutz C Berwanger, Petra Kolkhof, Boris Maček, Michael J Rust, Ilka M Axmann, Annegret Wilde.

The circadian clock of cyanobacteria, which predicts daily environmental changes, typically includes a standard oscillator consisting of proteins KaiA, KaiB, and KaiC. However, several cyanobacteria have diverse Kai protein homologs of unclear function. In particular, Synechocystis sp. PCC 6803 harbours, in addition to a canonical kaiABC gene cluster (named kaiAB1C1), two further kaiB and kaiC homologs (kaiB2, kaiB3, kaiC2, kaiC3). Here, we identify a chimeric KaiA homolog, named KaiA3, encoded by a gene located upstream of kaiB3. At the N-terminus, KaiA3 is similar to response-regulator receiver domains, whereas its C-terminal domain resembles that of KaiA. Homology analysis shows that a KaiA3-KaiB3-KaiC3 system exists in several cyanobacteria and other bacteria. Using the Synechocystis sp. PCC 6803 homologs, we observe circadian oscillations in KaiC3 phosphorylation in vitro in the presence of KaiA3 and KaiB3. Mutations of kaiA3 affect KaiC3 phosphorylation, leading to growth defects under both mixotrophic and chemoheterotrophic conditions. KaiC1 and KaiC3 exhibit phase-locked free-running phosphorylation rhythms. Deletion of either system (∆kaiAB1C1 or ∆kaiA3B3C3) alters the period of the cellular backscattering rhythm. Furthermore, both oscillators are required to maintain high-amplitude, self-sustained backscatter oscillations with a period of approximately 24 h, indicating their interconnected nature.

DOI: https://doi.org/10.1038/s41467-024-51914-5