Biology subjects

Golombek, D. A.

Publications and source records attributed to Golombek, D. A..

6 recordsLinked to original sources

bioRxiv2026

Circadian Disruption Drives Extracellular Matrix Remodeling to Facilitate Pulmonary Metastatic Colonization

Circadian clocks impose temporal architecture on signaling networks, and disruption of this architecture predisposes to cancer metastasis. Through direct pharmacological and genetic perturbation of core clock components, we establish that circadian desynchronization in mouse lung fibroblasts eliminates temporal migration gating, creating constitutive motility responses to TNF- and TGF-{beta}, and identify YAP/TEAD as the obligate, non-redundant convergence node through which clock-regulated ECM mechanical signals and cytokine-driven transcriptional programs jointly drive cellular motility. Chronic jet lag (CJL) in mice generates nocturnal TNF- elevation (ZT12-21) that drives sustained matrix metalloprotease expression while simultaneously reorganizing Hippo and TGF-{beta} signaling toward temporal convergence during daytime hours, enabling YAP/TEAD-dependent transcription to synergize with TGF-{beta} signaling and drive epithelial-to-mesenchymal transition (EMT) programs that normally remain temporally restricted. Functional validation demonstrates CJL doubles metastatic colonization incidence (40% to 90%) following B16F10 melanoma inoculation. Critically, established metastases amplify these molecular changes: metastatic burden under CJL creates maximal TGF-{beta} expression (ZT15-21), constitutive YAP activity, and sustained EMT marker expression, while eliminating M1/M2 macrophage temporal organization. Analysis of TCGA-SKCM metastatic melanoma datasets confirms that clock-disrupted human tumors exhibit selective strengthening of YAP/TAZ, EMT, and inflammatory pathway coupling, establishing that this convergence architecture is conserved in human disease. Together, these findings demonstrate that circadian disruption transforms from a facilitator of initial metastatic colonization into a driver of progressive metastatic burden by eliminating the temporal segregation that normally constrains pro-metastatic programs to discrete, non-overlapping windows, creating self-perpetuating cycles wherein pathway convergence facilitates colonization and established tumors amplify pro-metastatic signaling to maintain permissive microenvironmental conditions.

cancer biology↗

bioRxiv2026

Lunar gravity predicts sleep timing

Biological rhythms are fundamental to survival, synchronizing physiological and behavioural processes like the sleep-wake cycle with predictable environmental cycles like the solar day1. However, the extent to which human sleep responds to the lunar cycle remains a subject of controversy, particularly given the ubiquity of artificial light and conflicting reports regarding the influence of moonlight2-5. While lunar illuminance has been the primary candidate for such modulation, it fails to account for semilunar rhythms2,6 or effects observed during the dark new moon phase2,7. Here, we show that human and non-human primate sleep timing is synchronized with the gravimetric cycles exerted by the Moon and Sun. By analysing longitudinal actigraphic recordings from urban cohorts in Seattle, indigenous Toba/Qom communities in Argentina, and captive titi monkeys with attenuated access to natural light, we found that sleep onset is consistently delayed around periods of maximal gravitational variations. Crucially, this synchronization aligns with gravimetric peaks regardless of whether they occur at the full or new moon. Furthermore, while human sleep timing is heavily influenced by social constraints and self-selected light exposure, this synchronization persists in titi monkeys, in which these confounds are absent. These findings identify lunar gravity as a distinct environmental cue that may regulate sleep-wake behaviour. Although this regulation may be mediated by other geophysical factors oscillating with lunisolar gravitational tides, the results suggest that the mechanism is an evolutionarily conserved trait that shapes biological timing beyond the influence of light.

animal behavior and cognition↗

bioRxiv2025

Modern Times: Longitudinal Study of Toba/Qom Communities Reveals Delay and Shortening of Sleep in Real-Time Across Electrification

While artificial light and digital technologies are widely assumed to delay and curtail sleep, direct, longitudinal evidence documenting these changes is remarkably scarce. From 2012 to 2024, we conducted a longitudinal study of native Toba/Qom communities in northern Argentina, including rural groups newly introduced to electricity and semi-urban groups with earlier access to electricity. Using linear mixed-effects models on a dataset of over 12,000 actigraphically recorded sleep events from 156 participants at different times, we observed striking shifts in sleep dynamics. Remarkably, both groups showed delays of up to 1.4 hours in sleep timing, and participants from rural communities lost a full hour of sleep within just a decade. These changes occurred across a period that included, first, the introduction of electricity to rural communities after 2016, and, in more recent years, the spread of the internet and smartphone use among the Toba/Qom. Our models reveal that these events alone cannot fully explain the observed shifts in sleep timing, suggesting that broader processes of modernization and acculturation, beyond electric light and digital devices alone, may be driving sleep changes. The rapid transformations observed in these communities mirror, within a single decade, the likely trajectory of human sleep across the 20th and early 21st centuries, underscoring the complex ways modern environments reshape sleep behavior.

physiology↗

bioRxiv2023

Circadian regulation of MGMT expression and promoter methylation underlies daily rhythms in TMZ sensitivity in glioblastoma

BackgroundGlioblastoma (GBM) is the most common primary brain tumor in adults. Despite extensive research and clinical trials, median survival post-treatment remains at 15 months. Thus, all opportunities to optimize current treatments and improve patient outcomes should be considered. A recent retrospective clinical study found that taking TMZ in the morning compared to the evening was associated with a 6-month increase in median survival in patients with MGMT-methylated GBM. Here, we hypothesized that TMZ efficacy depends on time-of-day and O6-Methylguanine-DNA Methyltransferase (MGMT) activity in murine and human models of GBM. Methods and ResultsIn vitro recordings using real-time bioluminescence reporters revealed that GBM cells have intrinsic circadian rhythms in the expression of the core circadian clock genes Bmal1 and Per2, as well as in the DNA repair enzyme, MGMT. Independent measures of MGMT transcript levels and promoter methylation also showed daily rhythms intrinsic to GBM cells. These cells were more susceptible to TMZ when delivered at the daily peak of Bmal1 transcription. We found that in vivo morning administration of TMZ also decreased tumor size and increased body weight compared to evening drug delivery in mice bearing GBM xenografts. Finally, inhibition of MGMT activity with O6-Benzylguanine abrogated the daily rhythm in sensitivity to TMZ in vitro by increasing sensitivity at both the peak and trough of Bmal1 expression. ConclusionWe conclude that chemotherapy with TMZ can be dramatically enhanced by delivering at the daily maximum of tumor Bmal1 expression and minimum of MGMT activity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=164 SRC="FIGDIR/small/557630v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@2e9058org.highwire.dtl.DTLVardef@1069917org.highwire.dtl.DTLVardef@2cf000org.highwire.dtl.DTLVardef@40abc9_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Regulation of the circadian clock in C. elegans by clock gene homologs kin-20 and lin-42

Circadian rhythms are endogenous oscillations present in nearly all organisms from prokaryotes to humans, allowing them to adapt to cyclical environments close to 24 hours. Circadian rhythms are regulated by a central clock, which is based on a transcription-translation feedback loop. One important protein in the central loop in metazoan clocks is PERIOD, which is regulated in part by Casein kinase 1{varepsilon}/{delta} (CK1{varepsilon}/{delta}) phosphorylation. In the nematode Caenorhabditis elegans, period and casein kinase 1{varepsilon}/{delta} are conserved as lin-42 and kin-20, respectively. Here we studied the involvement of lin-42 and kin-20 in circadian rhythms of the adult nematode using a bioluminescence-based circadian transcriptional reporter. We show that mutations of lin-42 and kin-20 generate a significantly longer endogenous period, suggesting a role for both genes in the nematode circadian clock, as in other organisms. These phenotypes can be partially rescued by overexpression of either gene under their native promoter. Both proteins are expressed in neurons and seam cells, a population of epidermal stem cells in C. elegans that undergo multiple divisions during development. Depletion of LIN-42 and KIN-20 specifically in neuronal cells after development was sufficient to lengthen the period of oscillating sur-5 expression. Therefore, we conclude that LIN-42 and KIN-20 are critical regulators of the adult nematode circadian clock through neuronal cells.

neuroscience↗

bioRxiv2019

The methyl cycle is a conserved regulator of biological clocks.

The methyl cycle is a universally conserved metabolic pathway operating in prokaryotes and eukaryotes. In this pathway, the amino acid methionine is used to synthesize S-adenosylmethionine, the methyl donor co-substrate in the methylation of nucleic acids, histone and non-histone proteins and many other molecules within the cell. The methylation of nucleic acids and proteins is the foundation of epigenetic and epitranscriptomic regulations of gene expression, but whether the methyl cycle centrally regulates gene expression and function by controlling the availability of methyl moieties is poorly understood.\n\nFrom cyanobacteria to humans, a circadian clock that involves an exquisitely regulated transcription-translation-feedback loop driving oscillations in gene expression and orchestrating physiology and behavior has been described. We reported previously that inhibition of the methyl cycle in mammalian cells caused the lengthening of the period of these oscillations, suggesting the methyl cycle may indeed act as a central regulator of gene expression, at least in mammals. Here, we investigated whether the methyl cycle, given its universal presence among living beings, regulates the circadian clock in species across the phylogenetic tree of life.\n\nWe reveal a remarkable evolutionary conservation of the link between the methyl cycle and the circadian clock. Moreover, we show that the methyl cycle also regulates the somite segmentation clock, another transcription-translation negative feedback loop-based timing mechanism that orchestrate embryonic development in vertebrates, highlighting the methyl cycle as a master regulator of biological clocks.\n\nSIGNIFICANCE STATEMENTHere we reveal that the methyl cycle, a universal metabolic pathway leading to the synthesis of S-adenosylmethionine, the methyl donor co-substrate in virtually all transmethylation reactions within the cell, is a conserved regulator of biological clocks. These discoveries highlight the methyl cycle as a metabolic hub that regulates gene expression via the availability of methyl moieties for the methylation of nucleic acids, proteins and many other molecules with the cell.

evolutionary biology↗