Biology subjects

Anafi, R.

Publications and source records attributed to Anafi, R..

3 recordsLinked to original sources

bioRxiv2025

Defining and detecting global transcriptional amplitude in circadian gene expression

Many genes exhibit circadian rhythms in expression. The amplitude of oscillation, both in core clock and circadian output genes, may differ from person to person. Mutations in core clock genes are known to alter global rhythmic properties, and researchers often informally discuss "circadian amplitude." Yet, it remains unclear whether, in the general population, differences in transcriptional amplitude are largely gene-specific, or if they reflect a global, transcriptome-wide pattern -- whether some individuals have globally higher or lower amplitude across the set of all rhythmic genes. We used Cosinor regression to reanalyze four human skin time-series transcriptomic datasets (paired epidermis/dermis samples, N=11, N=19) and found that, using either absolute or relative amplitude measures, distributions of gene amplitudes tended to cluster by subject. Using a non-parametric, permutation-based statistical test, we found that in many subjects this global amplitude trend was statistically significant (p [≤] 0.01). Furthermore, we found that when rhythmic genes were divided into two sets based on peak time (genes peaking before-noon and after-noon), the subjects global amplitude in one set predicted global amplitude in the other set (p [≤] 0.05). We also found that in the paired epidermis/dermis datasets, subjects global amplitude in epidermis predicted their global amplitude in the dermis (p [≤] 0.05). After identifying these trends in the skin datasets, we then found that evidence for subject-specific transcriptional rhythm strength replicated across 6 additional human time-course datasets from adipose, muscle, and blood. Perhaps surprisingly, across datasets, we found that neither established metrics of core clock transcriptional organization nor the amplitude of core clock transcription were strongly correlated with subject-specific global amplitude.

cell biology↗

bioRxiv2020

CRY1-CBS binding regulates circadian clock function and metabolism

Circadian disruption influences metabolic health. Metabolism modulates circadian function. However, the mechanisms coupling circadian rhythms and metabolism remain poorly understood. Here we report that Cystathionine {beta}-synthase (CBS), a central enzyme in one-carbon metabolism, functionally interacts with the core circadian protein Cryptochrome1 (CRY1). In cells, CBS augments CRY1 mediated repression of the CLOCK/BMAL1 complex and shortens circadian period. Notably, we find that mutant CBS-I278T protein, the most common cause of homocystinuria, does not bind CRY1 or regulate its repressor activity. Transgenic CbsZn/Zn mice, while maintaining circadian locomotor activity period, exhibit reduced circadian power and increased expression of E-BOX outputs. CBS function is reciprocally influenced by CRY1 binding. CRY1 modulates enzymatic activity of the CBS. Liver extracts from Cry1-/- mice show reduced CBS activity that normalizes after the addition of exogenous wild type (WT) CRY1. Metabolomic analysis of WT, CbsZn/Zn, Cry1-/-, and Cry2-/- samples highlights the metabolic importance of endogenous CRY1. We observed temporal variation in one-carbon and transsulfuration pathways attributable to CRY1 induced CBS activation. CBS-CRY1 binding provides a post-translational switch to modulate cellular circadian physiology and metabolic control.

molecular biology↗

bioRxiv2018

Population level rhythms in human skin: implications for circadian medicine

Skin is the largest organ in the body and serves important barrier, regulatory, and sensory functions. Like other tissues, skin is subject to temporal fluctuations in physiological responses under both homeostatic and stressed states. To gain insight into these fluctuations, we investigated the role of the circadian clock in the transcriptional regulation of epidermis using a hybrid experimental design, where a limited set of human subjects (n=20) were sampled throughout the 24 h cycle and a larger population (n=219) were sampled once. By looking at pairwise correlations of core clock genes in 298 skin samples, we found a robust circadian oscillator in skin at the population level. Encouraged by this, we used CYCLOPS to reconstruct the temporal order of all samples and identified hundreds of rhythmically-expressed genes at the population level in human skin. We compared these results with published time-series skin data from mouse and show strong concordance in circadian phase across species for both transcripts and pathways. Further, like blood, skin is readily accessible and a potential source of biomarkers. Using ZeitZeiger, we identified a biomarker set for human skin that is capable of reporting circadian phase to within 3 h from a single sample. In summary, we show rhythms in human skin that persist at the population scale and a path to develop robust single-sample circadian biomarkers.\n\nOne Sentence SummaryHuman epidermis shows strong circadian rhythms at the population scale and provides a better source for developing robust, single-sample circadian phase biomarkers than human blood.

systems biology↗