Zhang B et al. (2024) Nat Chem Biol "Acylspermidines are conserved mitochondrial sirtuin-dependent metabolites."

Bales TR, Schroeder FC, Mullmann J, Weiss RS, Fernandez IR, Zhang B, Ludewig AH

[Nat Chem Biol, 2024]

Sirtuins are nicotinamide adenine dinucleotide (NAD⁺)-dependent protein lysine deacylases regulating metabolism and stress responses; however, characterization of the removed acyl groups and their downstream metabolic fates remains incomplete. Here we employed untargeted comparative metabolomics to reinvestigate mitochondrial sirtuin biochemistry. First, we identified N-glutarylspermidines as metabolites downstream of the mitochondrial sirtuin SIR-2.3 in Caenorhabditis elegans and demonstrated that SIR-2.3 functions as a lysine deglutarylase and that N-glutarylspermidines can be derived from O-glutaryl-ADP-ribose. Subsequent targeted analysis of C. elegans, mouse and human metabolomes revealed a chemically diverse range of N-acylspermidines, and formation of N-succinylspermidines and/or N-glutarylspermidines was observed downstream of mammalian mitochondrial sirtuin SIRT5 in two cell lines, consistent with annotated functions of SIRT5. Finally, N-glutarylspermidines were found to adversely affect C. elegans lifespan and mammalian cell proliferation. Our results indicate that N-acylspermidines are conserved metabolites downstream of mitochondrial sirtuins that facilitate annotation of sirtuin enzymatic activities in vivo and may contribute to sirtuin-dependent phenotypes.

Zhang B et al. (2021) Ecol Lett "Directed movement changes coexistence outcomes in heterogeneous environments."

Ni WM, Hastings A, Lam KY, Zhang B, Zhai L, Fu Z, Collins KM, Lou Y, DeAngelis DL, Signorelli R

[Ecol Lett, 2021]

Understanding mechanisms of coexistence is a central topic in ecology. Mathematical analysis of models of competition between two identical species moving at different rates of symmetric diffusion in heterogeneous environments show that the slower mover excludes the faster one. The models have not been tested empirically and lack inclusions of a component of directed movement toward favourable areas. To address these gaps, we extended previous theory by explicitly including exploitable resource dynamics and directed movement. We tested the mathematical results experimentally using laboratory populations of the nematode worm, Caenorhabditis elegans. Our results not only support the previous theory that the species diffusing at a slower rate prevails in heterogeneous environments but also reveal that moderate levels of a directed movement component on top of the diffusive movement allow species to coexist. Our results broaden the theory of species coexistence in heterogeneous space and provide empirical confirmation of the mathematical predictions.

Zhang B et al. (2014) Biomicrofluidics "Microfluidic platform integrated with worm-counting setup for assessing manganese toxicity."

He Q, Chen Z, Li X, Yao M, Zhang L, Qin J, Zhang B, Li Y, Liu J, Yu Y

[Biomicrofluidics, 2014]

We reported a new microfluidic system integrated with worm responders for evaluating the environmental manganese toxicity. The micro device consists of worm loading units, worm observing chambers, and a radial concentration gradient generator (CGG). Eight T-shape worm loading units of the micro device were used to load the exact number of worms into the corresponding eight chambers with the assistance of worm responders and doorsills. The worm responder, as a key component, was employed for performing automated worm-counting assay through electric impedance sensing. This label-free and non-invasive worm-counting technique was applied to the microsystem for the first time. In addition, the disk-shaped CGG can generate a range of stepwise concentrations of the appointed chemical automatically and simultaneously. Due to the scalable architecture of radial CGG, it has the potential to increase the throughput of the assay. Dopaminergic (DAergic) neurotoxicity of manganese on C. elegans was quantitatively assessed via the observation of green fluorescence protein-tagged DAergic neurons of the strain BZ555 on-chip. In addition, oxidative stress triggered by manganese was evaluated by the quantitative fluorescence intensity of the strain CL2166. By scoring the survival ratio and stroke frequency of worms, we characterized the dose- and time-dependent mobility defects of the manganese-exposed worms. Furthermore, we applied the microsystem to investigate the effect of natural antioxidants to protect manganese-induced toxicity.

Zhang, B. et al. (2019) International Worm Meeting "Toward imaging the chromatin dynamics at specific loci in C. elegans."

Ward, J., L'Etoile, N., Zhang, B., Huang, B., Chen, B.

[International Worm Meeting, 2019]

Gene expression is regulated dynamically during development. The conformation of chromatin as well as its modifications regulate the transcriptional activity of genes. Studies have shown that some sites of euchromatin (which is usually transcriptionally active) can switch to the typically inactive heterochromatic state under specific developmental signaling cues, and vice versa (Oberdoerffer & Sinclair, 2007; Trojer & Reinberg, 2007). Though such chromatin dynamics contribute to developmental processes, whether they underlie behavioral plasticity is unknown. Previous studies in our lab have demonstrated that in AWC olfactory sensory neurons of C. elegans, odr-1, which encodes a guanylyl cyclase, is repressed in odor-adapted animals (Juang et al., 2013). In addition, we also observed increased binding of the heterochromatin associated factor HPL-2 at the odr-1 locus in AWC as a result of odor adaptation. This suggests that the repression of odr-1 expression might be due to changes in chromatin conformation. We plan to develop a CRISPR-based fluorescence imaging technique to facilitate monitoring of the dynamic changes in chromatin structure at specific loci, such as odr-1. By targeting multiple copies of fluorescent proteins to specific sites in genome with the dCas9-based system, we can label regions of the genome and follow their dynamic changes in the subnuclear localization in C. elegans. We hope that this tool will help us better understand the subnuclear dynamics and organization of the genome during development in live animals in future.

Zhang B et al. (2020) Electrophoresis "An integrated microfluidics for assessing the anti-aging effect of caffeic acid phenethylester in Caenorhabditis elegans."

Sun D, Li Y, Zhang B, Chen Z, Zhuang L

[Electrophoresis, 2020]

Aging is a fundamental and fascinating process. Anti-aging research tried to find the mysteries about the human lifespan. To investigate the the longevity-extending role of caffeic acid phenethylester (CAPE) and reveal the possible regulation mechanism, the long-term cultivation under well-defined environments, real-time monitoring and live imaging is highly desired. In this paper, a well-designed microfluidic device was proposed to analyze the anti-aging effect of CAPE in Caenorhabditis elegans (C. elegans). With the combined use of multiple functional units, including micro-pillar, worm responder, a branching network of distribution channels and micro chambers, the longitudinal measurements of the exact number of worms throughout the whole lifespans is possible. Meanwhile, the brief cooling function of temperature-controllable system can achieve temporary and repeated immobilization of nematodes for fluorescence imaging. Our research data showed that CAPE can increase the survival of worms under normal and stress condition, including heat stress and paraquat-induced oxidative stress. The further studies revealed the anti-aging mechanism of CAPE. This proposed strategy and device would be a useful platform to facilitate future anti-aging studies and the finding of new lead compounds. This article is protected by copyright. All rights reserved.

Zhang B et al. (1997) Nature "A conserved RNA-binding protein that regulates sexual fates in the C. elegans hermaphrodite germ line."

Zhang B, Fields S, Wickens MP, Durkin E, Gallegos ME, Kimble JE, Puoti AR

[Nature, 1997]

The nematode Caenorhabditis elegans has two sexes, males and hermaphrodites. Hermaphrodites Initially produce sperm but switch to producing oocytes. This switch appears to be controlled by the 3' untranslated region of fem-3 messenger RNA. We have now identified a binding factor (FBF) which is a cytoplasmic protein that binds specifically to the regulatory region of fem-3 3'UTR and mediates the sperm/oocyte switch. The RNA-binding domain of FBF consists of a stretch of eight tandem repeats and two short flanking regions. This structural element is conserved in several proteins including Drosophila Pumilio, a regulatory protein that controls pattern formation in the fly by binding to a 3'UTR. We propose that FBF and Pumilio are members of a widespread family of sequence-specific RNA-binding proteins.

Zhang B et al. (2015) Cell Rep "Environmental Temperature Differentially Modulates C. elegans Longevity through a Thermosensitive TRP Channel."

Liu J, Xu XZ, He Y, Ronan EA, Zhang B, Xiao R, Hsu AL

[Cell Rep, 2015]

Temperature profoundly affects aging in both poikilotherms and homeotherms. A general belief is that lower temperatures extend lifespan, whereas higher temperatures shorten it. Although this "temperature law" is widely accepted, it has not been extensively tested. Here, we systematically evaluated the role of temperature in lifespan regulation in C. elegans. We found that, although exposure to low temperatures at the adult stage prolongs lifespan, low-temperature treatment at the larval stage surprisingly reduces lifespan. Interestingly, this differential effect of temperature on longevity in larvae and adults is mediated by the same thermosensitive TRP channel TRPA-1 that signals to the transcription factor DAF-16/FOXO. DAF-16/FOXO and TRPA-1 act in larva to shorten lifespan but extend lifespan in adulthood. DAF-16/FOXO differentially regulates gene expression in larva and adult in a temperature-dependent manner. Our results uncover complexity underlying temperature modulation of longevity, demonstrating that temperature differentially regulates lifespan at different stages of life.

Zhang B et al. (2021) Nat Aging "Olfactory perception of food abundance regulates dietary restriction-mediated longevity via a brain-to-gut signal."

Wu J, Jun H, Liu J, Shawn Xu XZ, Zhang B

[Nat Aging, 2021]

The role of food nutrients in mediating the positive effect of dietary restriction (DR) on longevity has been extensively characterized, but how non-nutrient food components regulate lifespan is not well understood. Here, we show that food-associated odors shorten the lifespan of <i>C. elegans</i> under DR but not those fed <i>ad libitum</i>, revealing a specific effect of food odors on DR-mediated longevity. Food odors act on a neural circuit comprising the sensory neurons ADF and CEP, and the interneuron RIC. This olfactory circuit signals the gut to suppress DR-mediated longevity via octopamine, the mammalian homolog of norepinephrine, by regulating the energy sensor AMPK through a Gq-PLC-CaMKK-dependent mechanism. In mouse primary cells, we find that norepinephrine signaling regulates AMPK through a similar mechanism. Our results identify a brain-gut axis that regulates DR-mediated longevity by relaying olfactory information about food abundance from the brain to the gut.

Zhang B et al. (2018) Genes Dev "Brain-gut communications via distinct neuroendocrine signals bidirectionally regulate longevity inC. elegans."

Zhang W, Liu J, Gong J, Xiao R, Xu XZS, Zhang B

[Genes Dev, 2018]

Tissue-tissue communications are integral to organismal aging, orchestrating a body-wide aging process. The brain plays a key role in this process by detecting and processing signals from the environment and then communicating them to distal tissues such as the gut to regulate longevity. How this is achieved, however, is poorly understood. Here, using<i>Caenorhabditis elegans</i>as a model, we identified two distinct neuroendocrine signaling circuits by which the worm nervous system senses cool and warm environmental temperatures through cool- and warm-sensitive neurons and then signals the gut to extend and shorten life span, respectively. The prolongevity &quot;cool&quot; circuit uses the small neurotransmitters glutamate and serotonin, whereas the anti-longevity &quot;warm&quot; circuit is mediated by insulin-like neuropeptides. Both types of neuroendocrine signals converge on the gut through their cognate receptors to differentially regulate the transcription factor DAF-16/FOXO, leading to opposing outcomes in longevity. Our study illustrates how the brain detects and processes environmental signals to bidirectionally regulate longevity by signaling the gut.

Zhang B et al. (2024) Proc Natl Acad Sci U S A "Amino acid and protein specificity of protein fatty acylation in C. elegans."

Liu Y, Zhang B, Schroeder FC, Fox BW, Lin H, Thirumalaikumar VP, Skirycz A, Yu Y

[Proc Natl Acad Sci U S A, 2024]

Protein lipidation plays critical roles in regulating protein function and localization. However, the chemical diversity and specificity of fatty acyl group utilization have not been investigated using untargeted approaches, and it is unclear to what extent structures and biosynthetic origins of <i>S</i>-acyl moieties differ from <i>N</i>- and <i>O</i>-fatty acylation. Here, we show that fatty acylation patterns in <i>Caenorhabditis elegans</i> differ markedly between different amino acid residues. Hydroxylamine capture revealed predominant cysteine <i>S</i>-acylation with 15-methylhexadecanoic acid (isoC17:0), a monomethyl branched-chain fatty acid (mmBCFA) derived from endogenous leucine catabolism. In contrast, enzymatic protein hydrolysis showed that N-terminal glycine was acylated almost exclusively with straight-chain myristic acid, whereas lysine was acylated preferentially with two different mmBCFAs and serine was acylated promiscuously with a broad range of fatty acids, including eicosapentaenoic acid. Global profiling of fatty acylated proteins using a set of click chemistry-capable alkyne probes for branched- and straight-chain fatty acids uncovered 1,013 <i>S</i>-acylated proteins and 510 hydroxylamine-resistant <i>N</i>- or <i>O</i>-acylated proteins. Subsets of <i>S</i>-acylated proteins were labeled almost exclusively by either a branched-chain or a straight-chain probe, demonstrating acylation specificity at the protein level. Acylation specificity was confirmed for selected examples, including the <i>S</i>-acyltransferase DHHC-10. Last, homology searches for the identified acylated proteins revealed a high degree of conservation of acylation site patterns across metazoa. Our results show that protein fatty acylation patterns integrate distinct branches of lipid metabolism in a residue- and protein-specific manner, providing a basis for mechanistic studies at both the amino acid and protein levels.