Daily liver rhythms: Coupling morphological and molecular oscillations

Ueli Schibler ¹, Flore Sinturel ², Felix Naef ³, Alan Gerber ^4 5, David Gatfield ⁶

. 2025 Sep 9;122(36):e2517648122.

 doi: 10.1073/pnas.2517648122. Epub 2025 Aug 29.

• PMID: 40880543
• PMCID: PMC12435289 (available on 2026-03-01)
• DOI: 10.1073/pnas.2517648122

Abstract

In mammals, a hierarchically organized circadian timing system orchestrates daily rhythms of nearly all physiology. A master pacemaker in the brain’s suprachiasmatic nucleus (SCN) synchronizes subsidiary clocks in most peripheral organs. By driving anabolic and catabolic cycles of proteins, lipids, and carbohydrates and by detoxifying endo- and xenobiotic components, the liver plays an important role in adapting the metabolic needs to rest-activity rhythms. In keeping with these functions, the liver expresses many clock-controlled genes that are required for these processes. Remarkably, however, this organ also fluctuates in size and morphological parameters. In mice, the mass of the liver increases and decreases by 30 to 40% during the 24-h day. The oscillation in liver mass is accompanied by daily rhythms of similar amplitudes in hepatocyte cell size and global RNA and protein accumulation. The number of ribosomes, which parallels the ups and downs of liver size, appears to be the rate-limiting factor in driving the diurnal rhythms of overall protein synthesis. Obviously, the rapid increase in hepatocyte size within the liver engenders mechanical stress, which must be dealt with by increasing the physical robustness of cells. Indeed, the actin cytoskeleton of hepatocytes undergoes dramatic polymerization cycles. Thus, massive intracellular and subcortical F-actin bundles are assembled during the night, at which the liver reaches its maximal size. In turn, the oscillation in actin polymerization elicits rhythms in myocardin-related transcription factors-serum response factor signaling, which participate in the circadian transcription of the core clock gene Per2 and thereby contribute to the synchronization of hepatocyte clocks.

Hypothalamic Astrocytes Exhibit Glycolytic Features Making Them Prone for Glucose Sensing

Sarah Geller ^1 2, Nadège Zanou ^3 4, Sylviane Lagarrigue ⁴, Tamara Zehnder ⁵, Cathy Gouelle ^4 5, Tania Santoro ^1 6, Cendrine Repond ⁴, Paola Bezzi ^5 7, Francesca Amati ^4 8, Anne-Karine Bouzier-Sore ⁹, Ariane Sharif ¹⁰, Luc Pellerin ^1 11

. 2025 Nov;73(11):2253-2272.

 doi: 10.1002/glia.70066. Epub 2025 Jul 24.

• PMID: 40708167
• PMCID: PMC12436996
• DOI: 10.1002/glia.70066

Abstract

In the hypothalamus, detection of energy substrates such as glucose is essential to regulate food intake and peripheral energy homeostasis. Metabolic interactions between astrocytes and neurons via lactate exchange have been proposed as a hypothalamic glucose-sensing mechanism, but the molecular basis remains uncertain. Mouse hypothalamic astrocytes in vitro were found to exhibit a stronger glycolytic phenotype in basal conditions than cortical astrocytes. It was associated with higher protein expression levels of the Pyruvate Kinase Isoform M2 (Pkm2) and its more prominent nuclear localization. In parallel, hypothalamic astrocytes also expressed higher levels of the monocarboxylate transporter Slc16a3 (Mct4), which were dependent on Pkm2 expression. The stronger Mct4 expression in hypothalamic versus cortical astrocytes is an intrinsic characteristic, as it was also present after their direct isolation from adult mouse tissue. The high lactate release capacity of hypothalamic astrocytes was demonstrated to depend on the expression of Mct4, but not Mct1. Unlike cortical astrocytes, hypothalamic astrocytes in culture do not respond to glutamate with enhanced glycolysis, but instead, they modulate their lactate production according to glucose concentrations in an AMPK-dependent manner, an effect observed in both mouse and human hypothalamic astrocytes in vitro. Our study shows that hypothalamic and cortical astrocytes are geared to have distinct glycolytic responses to glucose and glutamate, respectively. These results reveal a metabolic specialization of astrocytes in order to fulfill distinct area-specific functions: glucose-sensing in the hypothalamus versus activity-dependent neuronal energetic supply in cortical regions.

Translon: a single term for translated regions

PMID: 40890551
 DOI: 10.1038/s41592-025-02810-3

Early Flowering 3 (ELF3) Inhibits Hypocotyl Phototropism in Light-Grown Arabidopsis Seedlings

Geoffrey M C Cobb ¹, Johanna Krahmer ^1 2, Ganesh M Nawkar ^1 3, Alessandra Boccaccini ^1 4, Sandi Paulišić ¹, Christian Fankhauser ¹

. 2025 Sep 23;9(9):e70107.

 doi: 10.1002/pld3.70107. eCollection 2025 Sep.

• PMID: 40995069
• PMCID: PMC12455371
• DOI: 10.1002/pld3.70107

Abstract

Phototropic bending of plants towards a light source allows them to position their photosynthetic tissues to optimize light capture. In light-grown (de-etiolated) Arabidopsis seedlings, phototropic bending of the hypocotyl is inhibited by light with a high red:far-red ratio (HRFR) and high levels of blue light (HBL). This occurs via activation of the phytochrome B (phyB) and cryptochrome 1 (cry1) photoreceptor signaling pathways. Both phyB and cry1 act upstream of PHYTOCHROME INTERACTING FACTOR (PIF) transcription factors, which are required for hypocotyl bending in light-grown seedlings. Presently, it is not known whether other pathways are involved in the inhibition of PIF-mediated phototropism in light-grown seedlings. To address this, we conducted a screen to identify mutants with increased phototropic bending relative to wild type in HRFR + HBL conditions. Through this screen, we identified EARLY FLOWERING 3 (ELF3), a member of the Evening Complex (EC), as a key inhibitor of phototropic bending in green seedlings. We show that both ELF3 and LUX, another component of the EC, inhibit phototropic bending upstream of PIF4/PIF5. Furthermore, we show that phototropic bending in Arabidopsis seedlings is subject to circadian regulation in an ELF3-dependent manner. Finally, we provide evidence that ELF3 in the grass Brachypodium distachyon also affects phototropism but in an opposite way than in Arabidopsis.

Structured detection for simultaneous super-resolution and optical sectioning in laser scanning microscopy

Alessandro Zunino ^# 1, Giacomo Garrè ^# 1 2, Eleonora Perego ^1 3, Sabrina Zappone ^1 2, Mattia Donato ¹, Nadine Vastenhouw ³, Giuseppe Vicidomini ¹

. 2025;19(8):888-897.

 doi: 10.1038/s41566-025-01695-0. Epub 2025 Jun 5.

• PMID: 40823346
• PMCID: PMC12353846
• DOI: 10.1038/s41566-025-01695-0

Abstract

Fast detector arrays enable an effective implementation of image scanning microscopy, which overcomes the trade-off between spatial resolution and signal-to-noise ratio of confocal microscopy. However, current image scanning microscopy approaches do not provide optical sectioning and fail with thick samples unless the detector size is limited, thereby introducing a new trade-off between optical sectioning and signal-to-noise ratio. Here we propose a method that overcomes such a limitation. From single-plane acquisition, we reconstruct an image with digital and optical super-resolution, high signal-to-noise ratio and enhanced optical sectioning. On the basis of the observation that imaging with a detector array inherently embeds axial information, we designed a straightforward reconstruction algorithm that inverts the physical model of image scanning microscopy image formation. We present a comprehensive theoretical framework and validate our method with images of biological samples captured using a custom setup equipped with a single-photon avalanche diode array detector. We demonstrate the feasibility of our approach by exciting fluorescence emission in both linear and nonlinear regimes. Moreover, we generalize the algorithm for fluorescence lifetime imaging, fully exploiting the single-photon timing ability of the single-photon avalanche diode array detector. Our method outperforms conventional reconstruction techniques and can be extended to any laser scanning microscopy technique.

Specificity in clustering of gene-specific transcription factors is encoded in the genome

Shivali Dongre ¹, Nadine L Vastenhouw ¹

. 2025 Jul 8;53(13):gkaf625.

 doi: 10.1093/nar/gkaf625.

• PMID: 40650976
• PMCID: PMC12255298
• DOI: 10.1093/nar/gkaf625

Abstract

Gene-specific transcription factors (TFs) often form clusters in the nucleus. Such clusters can facilitate transcription, but it remains unclear how they form. It has been suggested that clusters are seeded by the sequence-specific binding of TFs to DNA and grow by interactions between intrinsically disordered regions (IDRs) that bring in more TFs. In this model, specificity in TF clustering must be provided by the IDRs. To investigate this model, we studied TF clustering by quantitative imaging of Nanog, Pou5f3, and Sox19b in zebrafish embryos. Using mutant TFs, we show that the formation of a TF cluster requires the DNA-binding domain (DBD) as well as at least one of its IDRs. Importantly, IDRs are not sufficient to join a pre-existing cluster. Rather, both IDR and DBD are needed. Finally, using chimeric TFs, we show that while IDRs are required to join a cluster, they are quite promiscuous, and it is the DBD that provides specificity to the clustering of a TF. Thus, for any TF to join a cluster, motif recognition is required, which explains the specificity in TF cluster formation. Taken together, our work provides an alternative model for how specificity is achieved in the organization of transcriptional machinery in the nucleus.

© The Author(s) 2025. Published by Oxford University Press on behalf of Nucleic Acids Research.