Biology subjects

Moller-Levet, C. S.

Publications and source records attributed to Moller-Levet, C. S..

4 recordsLinked to original sources

bioRxiv2025

Performance of blood-based biomarkers for human circadian pacemaker phase: Training sets matter as much as feature selection methods

Biomarkers are valuable tools in a wide range of human health areas including circadian medicine. Valid, low burden, multivariate molecular approaches to assess circadian phase at scale in people living and working in the real-world hold promise for translating basic circadian knowledge to practical applications. However, standards for the development and evaluation of these circadian biomarkers have not yet been established, even though several publications report such biomarkers and claim that the methods are universal. Here we present a basic exploration of some of the determinants and confounds of blood-based biomarker development for SCN phase by reanalysing publicly available data sets. We compare performance of biomarkers based on three feature selection methods: Partial Least Squares Regression, ZeitZeiger and Elastic Net, as well as performance of a standard set of clock genes. We explore the effects of training sample size and the impact of the experimental protocols from which training samples are drawn and on which performance is tested. Approaches based on small sample sizes used for training are prone to poor performance due to overfitting. Performance to some extent depends on the feature selection method, but at least as much on the experimental conditions from which the biomarker training samples were drawn. Performance of biomarkers developed under baseline conditions do not necessarily translate to protocols that mimic real world scenarios such as shiftwork in which sleep may be restricted or desynchronised from endogenous circadian SCN phase. The molecular features selected by the various approaches to develop biomarkers for SCN phase show very little overlap, although the processes associated with these features have common themes with response to steroid hormones, i.e. cortisol being the most prominent. Overall, the findings indicate that establishment of circadian biomarkers should be guided by established biomarker development concepts and foundational principles of human circadian biology.

bioinformatics↗

bioRxiv2021

Overlap of expression and alignment of diurnal and circadian rhythmicity in the human blood transcriptome with organ and tissue specific rhythmicity in a non-human primate

BACKGROUNDTwenty-four-hour rhythmicity in transcriptomes of tissues and organs is driven by local circadian oscillators, systemic factors, the central circadian pacemaker, and light-dark cycles. This rhythmicity is to some extent organ- and tissue-specific such that the sets of rhythmic transcripts or their timing are different across tissues/organs. Monitoring rhythmicity of tissues and organs holds promise for circadian medicine, but in humans most tissues and organs are not easily accessible. To investigate the extent to which rhythmicity in the human blood transcriptome reflects rhythmicity in tissues and organs, we compared the overlap and timing of rhythmic transcripts in human blood and rhythmic transcripts in 64 tissues/organs of the baboon. METHODSRhythmicity in the transcriptomes of humans and baboons were compared using set logic, circular cross-correlation, circular clustering, functional enrichment analyses and partial least squares regression. RESULTSOf the 759 orthologous genes that were rhythmic in human blood, 652 (86%) were also rhythmic in at least one baboon tissue. Most of these genes were associated with basic processes such as transcription and protein homeostasis. 109 (17%) of the 652 overlapping rhythmic genes were reported as rhythmic in only one baboon tissue or organ and several of these genes have tissue/organ-specific functions. Analysis of the alignment between baboon and human transcriptomes showed that in these diurnal species, rhythmicity is aligned with the onset, rather than midpoint or end of light period. In both species, the timing of rhythmic transcripts displayed prominent night and day clusters, with genes in the dark cluster associated with translation. The timing of human and baboon transcriptomes was significantly correlated in 25 tissue/organs with an average earlier timing of 3.21 h (SD 2.47 h) in human blood. CONCLUSIONSThe human blood transcriptome contains sets of rhythmic genes that overlap with rhythmic genes of tissues/organs, some of which are tissue/organ-specific, in the baboon. The rhythmic sets vary across tissues/organs but the timing of most rhythmic genes is similar across human blood and baboon tissues/organs. These results have implications for our understanding of the regulation of rhythmicity across tissues/organs and species and development of blood transcriptome-based biomarkers for rhythmicity in tissues and organs.

molecular biology↗

bioRxiv2018

REM sleep: unique associations with behavior, corticosterone regulation and apoptotic pathways in chronic stress in mice

One of sleeps putative functions is mediation of adaptation to waking experiences. Chronic stress is a common waking experience, however, which specific aspect of sleep is most responsive, and how sleep changes relate to behavioral disturbances and molecular correlates remain unknown. We quantified sleep, physical, endocrine and behavioral variables and the brain and blood transcriptome in mice exposed to nine weeks of unpredictable chronic mild stress (UCMS). Comparing 46 phenotypical variables revealed that rapid-eye-movement sleep (REMS), corticosterone regulation and coat state were most responsive to UCMS. REMS theta oscillations were enhanced whereas delta oscillations in non-REMS were unaffected. Transcripts affected by UCMS in the prefrontal cortex, hippocampus, hypothalamus and blood were associated with inflammatory and immune responses. A machine learning approach controlling for unspecific UCMS effects identified transcriptomic predictors for specific phenotypes and their overlap. Transcriptomic predictor sets for the inter-individual variation in REMS continuity and theta activity shared many pathways with corticosterone regulation and in particular pathways implicated in apoptosis, including mitochondrial pathways. Predictor sets for REMS and anhedonia, one of the behavioral changes following UCMS, shared pathways involved in oxidative stress, cell proliferation and apoptosis. RNA predictor sets for non-NREMS parameters showed no overlap with other phenotypes. These novel data identify REMS as a core and early element of the response to chronic stress, and identify apoptotic pathways as a putative mechanism by which REMS mediates adaptation to stressful waking experiences.\n\nSignificance StatementSleep is responsive to experiences during wakefulness and is altered in stress-related disorders. Whether sleep changes primarily concern rapid-eye-movement sleep (REMS) or non-REM sleep, and how they correlate with stress hormones, behavioral and transcriptomic responses remained unknown. We demonstrate using unpredictable chronic (9-weeks) mild stress that REMS is the most responsive of all the measured sleep characteristics, and correlates with deficiency in corticosterone regulation. An unbiased machine learning, controlling for unspecific effects of stress, revealed that REMS correlated with RNA predictor sets enriched in apoptosis including mitochondrial pathways. Several pathways were shared with predictors of corticosterone and behavioral responses. This unbiased approach point to apoptosis as a molecular mechanism by which REMS mediates adaptation to an ecologically relevant waking experience.

neuroscience↗

bioRxiv2018

Genome-wide analysis of the role of the antibiotic biosynthesis regulator AbsA2 in Streptomyces coelicolor A3(2)

The AbsA1-AbsA2 two component signalling system of Streptomyces coelicolor has long been known to exert a powerful negative influence on the production of the antibiotics actinorhodin, undecylprodiginine and the Calcium-Dependent Antibiotic (CDA). Here we report the analysis of a{Delta} absA2 deletion strain, which exhibits the classic precocious antibiotic hyper-production phenotype, and its complementation by an N-terminal triple-FLAG-tagged version of AbsA2. The complemented and non-complemented{Delta} absA2 mutant strains were used in large-scale microarray-based time-course experiments to investigate the effect of deleting absA2 on gene expression and to identify the in vivo AbsA2 DNA-binding target sites using ChIP-on chip. We show that in addition to binding to the promoter regions of redZ and actII-orfIV AbsA2 binds to several previously unidentified sites within the cda biosynthetic gene cluster within and/or upstream of SCO3215 - SCO3216, SCO3217, SCO3229 - SCO3230, and SCO3226, and we relate the pattern of AbsA2 binding to the results of the transcriptomic study and antibiotic phenotypic assays. Interestingly, dual biphasic ChIP peaks were observed with AbsA2 binding across the regulatory genes actII-orfIV and redZ and the absA2 gene itself, while more conventional single promoter-proximal peaks were seen at the CDA biosynthetic genes suggesting a different mechanism of regulation of the former loci. Taken together the results shed light on the complex mechanism of regulation of antibiotic biosynthesis in Streptomyces coelicolor and the important role of AbsA2 in controlling the expression of three antibiotic biosynthetic gene clusters.

genomics↗