Loss of SET1/COMPASS methyltransferase activity reduces lifespan and fertility in Caenorhabditis elegans

Changes in histone post-translational modifications are associated with aging through poorly defined mechanisms. Histone 3 lysine 4 (H3K4) methylation at promoters is deposited by SET1 family methyltransferases acting within conserved multiprotein complexes known as COMPASS. Previous work yielded conflicting results about the requirement for H3K4 methylation during aging. Here, we reassessed the role of SET1/COMPASS–dependent H3K4 methylation in Caenorhabditis elegans lifespan and fertility by generating set-2(syb2085) mutant animals that express a catalytically inactive form of SET-2, the C. elegans SET1 homolog. We show that set-2(syb2085) animals retain the ability to form COMPASS, but have a marked global loss of H3K4 di- and trimethylation (H3K4me2/3). Reduced H3K4 methylation was accompanied by loss of fertility, as expected; however, in contrast to earlier studies, set-2(syb2085) mutants displayed a significantly shortened, not extended, lifespan and had normal intestinal fat stores. Other commonly used set-2 mutants were also short-lived, as was a cfp-1 mutant that lacks the SET1/COMPASS chromatin-targeting component. These results challenge previously held views and establish that WT H3K4me2/3 levels are essential for normal lifespan in C. elegans.

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Loss of SET1/COMPASS methyltransferase activity reduces lifespan and fertility in Caenorhabditis elegans

10.1101/2021.06.07.447374 ◽

2021 ◽

Author(s):

Matthieu Caron ◽

Loic Gely ◽

Steven Garvis ◽

Annie Adrait ◽

Yohann Couté ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Model Organisms ◽

Lysine Methylation ◽

Post Translational Modification ◽

H3k4 Methylation ◽

C Elegans ◽

Histone 3 ◽

Inactive Form ◽

Extended Lifespan ◽

Fat Stores

Post-translational modification of histones, particularly lysine methylation, are thought to play a crucial role in the aging process. Histone 3 lysine 4 (H3K4) methylation, a modification associated with active chromatin, is mediated by a family of SET1 methyltransferases acting within conserved multiprotein complexes known as COMPASS. Previous work in model organisms with partial or complete deletion of COMPASS subunits has yielded conflicting results about the requirement for H3K4 methylation during aging. Here, we reassessed the role of SET1/COMPASS-dependent H3K4 methylation in Caenorhabditis elegans lifespan regulation and fertility by generating set-2(syb2085) mutant animals that express a catalytically inactive form of SET-2, the C. elegans homolog of SET1. We show that animals bearing catalytically inactive SET-2 retain the ability to form COMPASS complexes but have a marked global loss of H3K4 dimethylation and trimethylation. Consistent with previous work, reduced H3K4 methylation was accompanied by loss of fertility; however, in striking contrast to earlier studies, set-2(syb2085) mutants displayed a significantly shortened, not extended, lifespan and had normal intestinal fat stores. Furthermore, other commonly used set-2 mutants were also short-lived, as was a cfp-1 mutant that lacks a non-catalytic SET1/COMPASS component and displays reduced H3K4 methylation. These results challenge previously held views and establish that wild-type H3K4 methylation levels are necessary to achieve a normal lifespan in C. elegans.

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Characterization of Caenorhabditis elegans Homologs of the Down Syndrome Candidate Gene DYRK1A

Genetics ◽

10.1093/genetics/163.2.571 ◽

2003 ◽

Vol 163 (2) ◽

pp. 571-580 ◽

Cited By ~ 1

Author(s):

William B Raich ◽

Celine Moorman ◽

Clay O Lacefield ◽

Jonah Lehrer ◽

Dusan Bartsch ◽

...

Keyword(s):

Down Syndrome ◽

Caenorhabditis Elegans ◽

Trisomy 21 ◽

Gene Dosage ◽

Inducible Promoters ◽

C Elegans ◽

Dual Specificity ◽

Specificity Protein

Abstract The pathology of trisomy 21/Down syndrome includes cognitive and memory deficits. Increased expression of the dual-specificity protein kinase DYRK1A kinase (DYRK1A) appears to play a significant role in the neuropathology of Down syndrome. To shed light on the cellular role of DYRK1A and related genes we identified three DYRK/minibrain-like genes in the genome sequence of Caenorhabditis elegans, termed mbk-1, mbk-2, and hpk-1. We found these genes to be widely expressed and to localize to distinct subcellular compartments. We isolated deletion alleles in all three genes and show that loss of mbk-1, the gene most closely related to DYRK1A, causes no obvious defects, while another gene, mbk-2, is essential for viability. The overexpression of DYRK1A in Down syndrome led us to examine the effects of overexpression of its C. elegans ortholog mbk-1. We found that animals containing additional copies of the mbk-1 gene display behavioral defects in chemotaxis toward volatile chemoattractants and that the extent of these defects correlates with mbk-1 gene dosage. Using tissue-specific and inducible promoters, we show that additional copies of mbk-1 can impair olfaction cell-autonomously in mature, fully differentiated neurons and that this impairment is reversible. Our results suggest that increased gene dosage of human DYRK1A in trisomy 21 may disrupt the function of fully differentiated neurons and that this disruption is reversible.

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Potential role of protein stabilizers in amelioration of Parkinson's disease and associated effects in transgenic Caenorhabditis elegans model expressing alpha-synuclein

RSC Advances ◽

10.1039/c5ra13546j ◽

2015 ◽

Vol 5 (95) ◽

pp. 77706-77715 ◽

Cited By ~ 4

Author(s):

Supinder Kaur ◽

Aamir Nazir

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Caenorhabditis Elegans ◽

Potential Role ◽

Alpha Synuclein ◽

C Elegans

Studies employing transgenicC. elegansmodel show that trehalose, a protein stabilizer, alleviates manifestations associated with Parkinson's diseaseviaits inherent activity and through induction of autophagic machinery.

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Autophagosomes fuse to phagosomes and play important roles in the degradation of apoptotic cells in Caenorhabditis elegans

10.1101/2021.07.16.452694 ◽

2021 ◽

Author(s):

Omar Pena-Ramos ◽

Lucia Chiao ◽

Xianghua Liu ◽

Tianyou Yao ◽

Henry He ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Small Gtpase ◽

Apoptotic Cells ◽

Phagosome Maturation ◽

Double Membrane ◽

C Elegans ◽

Intracellular Organelles ◽

Intracellular Vesicles ◽

Cellular Components

Autophagosomes are double-membrane intracellular vesicles that degrade protein aggregates, intracellular organelles, and other cellular components. In the nematode Caenorhabditis elegans, 113 somatic cells undergo apoptosis during embryogenesis and are engulfed and degraded by their neighboring cells. We discovered a novel role of autophagosomes in facilitating the degradation of apoptotic cells in C. elegans embryos using a real-time imaging technique. Specifically, double-membrane autophagosomes in engulfing cells are recruited to the surfaces of phagosomes containing apoptotic cells and subsequently fuse to phagosomes, allowing the inner membrane to enter the phagosomal lumen. Mutants defective in the production of autophagosomes display significant delays in the degradation of apoptotic cells, demonstrating the important contribution of autophagosomes to this process. The signaling pathway led by the phagocytic receptor CED-1, CED-1s adaptor CED-6, and the large GTPase dynamin (DYN-1) promote the recruitment of autophagosomes to phagosomes. Moreover, the subsequent fusion of autophagosomes with phagosomes requires the functions of the small GTPase RAB-7 and the HOPS complex. Our findings reveal that, unlike the single-membrane, LC3- associated phagocytosis (LAP) vesicles reported for mammalian phagocytes, canonical autophagosomes function in the clearance of C. elegans apoptotic cells. These findings add autophagosomes to the collection of intracellular organelles that contribute to phagosome maturation, identify novel crosstalk between the autophagy and phagosome maturation pathways, and discover the upstream factors that initiate this crosstalk.

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Effects of NAD+ in Caenorhabditis elegans Models of Neuronal Damage

Biomolecules ◽

10.3390/biom10070993 ◽

2020 ◽

Vol 10 (7) ◽

pp. 993

Author(s):

Yuri Lee ◽

Hyeseon Jeong ◽

Kyung Hwan Park ◽

Kyung Won Kim

Keyword(s):

Caenorhabditis Elegans ◽

Therapeutic Strategy ◽

Axon Regeneration ◽

Neuronal Damage ◽

Biological Processes ◽

Nematode Caenorhabditis Elegans ◽

C Elegans ◽

Neuronal Functions ◽

Molecular Components

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor that mediates numerous biological processes in all living cells. Multiple NAD+ biosynthetic enzymes and NAD+-consuming enzymes are involved in neuroprotection and axon regeneration. The nematode Caenorhabditis elegans has served as a model to study the neuronal role of NAD+ because many molecular components regulating NAD+ are highly conserved. This review focuses on recent findings using C. elegans models of neuronal damage pertaining to the neuronal functions of NAD+ and its precursors, including a neuroprotective role against excitotoxicity and axon degeneration as well as an inhibitory role in axon regeneration. The regulation of NAD+ levels could be a promising therapeutic strategy to counter many neurodegenerative diseases, as well as neurotoxin-induced and traumatic neuronal damage.

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Aurora-A kinase is required for centrosome maturation in Caenorhabditis elegans

The Journal of Cell Biology ◽

10.1083/jcb.200108051 ◽

2001 ◽

Vol 155 (7) ◽

pp. 1109-1116 ◽

Cited By ~ 292

Author(s):

Eva Hannak ◽

Matthew Kirkham ◽

Anthony A. Hyman ◽

Karen Oegema

Keyword(s):

Caenorhabditis Elegans ◽

Fluorescence Intensity ◽

Maturation Process ◽

Aurora A Kinase ◽

Aurora A ◽

Wild Type ◽

C Elegans ◽

Nuclear Envelope Breakdown ◽

Pericentriolar Material

Centrosomes mature as cells enter mitosis, accumulating γ-tubulin and other pericentriolar material (PCM) components. This occurs concomitant with an increase in the number of centrosomally organized microtubules (MTs). Here, we use RNA-mediated interference (RNAi) to examine the role of the aurora-A kinase, AIR-1, during centrosome maturation in Caenorhabditis elegans. In air-1(RNAi) embryos, centrosomes separate normally, an event that occurs before maturation in C. elegans. After nuclear envelope breakdown, the separated centrosomes collapse together, and spindle assembly fails. In mitotic air-1(RNAi) embryos, centrosomal α-tubulin fluorescence intensity accumulates to only 40% of wild-type levels, suggesting a defect in the maturation process. Consistent with this hypothesis, we find that AIR-1 is required for the increase in centrosomal γ-tubulin and two other PCM components, ZYG-9 and CeGrip, as embryos enter mitosis. Furthermore, the AIR-1–dependent increase in centrosomal γ-tubulin does not require MTs. These results suggest that aurora-A kinases are required to execute a MT-independent pathway for the recruitment of PCM during centrosome maturation.

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Synthesis of paucimannose N-glycans by Caenorhabditis elegans requires prior actions of UDP-N-acetyl-d-glucosamine:alpha-3-d-mannoside beta1,2-N-acetylglucosaminyltransferase I, alpha3,6-mannosidase II and a specific membrane-bound beta-N-acetylglucosaminidase

Biochemical Journal ◽

10.1042/bj20021931 ◽

2003 ◽

Vol 372 (1) ◽

pp. 53-64 ◽

Cited By ~ 41

Author(s):

Wenli ZHANG ◽

Pinjiang CAO ◽

Shihao CHEN ◽

Andrew M. SPENCE ◽

Shaoxian ZHU ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Metal Ion ◽

Suitable Model ◽

Bivalent Metal ◽

C Elegans ◽

Membrane Bound ◽

Specific Membrane ◽

Optimal Ph ◽

Nematode Development

We have previously reported three Caenorhabditis elegans genes (gly-12, gly-13 and gly-14) encoding UDP-N-acetyl-d-glucosamine:α-3-d-mannoside β1,2-N-acetylglucosaminyltransferase I (GnT I), an enzyme essential for hybrid and complex N-glycan synthesis. GLY-13 was shown to be the major GnT I in worms and to be the only GnT I cloned to date which can act on [Manα1,6(Manα1,3)Manα1,6](Manα1,3)Manβ1, 4GlcNAcβ1,4GlcNAc-R, but not on Manα1,6(Manα1,3)Manβ1-O-R substrates. We now report the kinetic constants, bivalent-metal-ion requirements, and optimal pH, temperature and Mn2+ concentration for this unusual enzyme. C. elegans glycoproteins are rich in oligomannose (Man6–9GlcNAc2) and ‘paucimannose’ Man3–5GlcNAc2(±Fuc) N-glycans, but contain only small amounts of complex and hybrid N-glycans. We show that the synthesis of paucimannose Man3GlcNAc2 requires the prior actions of GnT I, α3,6-mannosidase II and a membrane-bound β-N-acetylglucosaminidase similar to an enzyme previously reported in insects. The β-N-acetylglucosaminidase removes terminal N-acetyl-d-glucosamine from the GlcNAcβ1, 2Manα1,3Manβ- arm of Manα1,6(GlcNAcβ1,2Manα1,3) Manβ1,4GlcNAcβ1,4GlcNAc-R to produce paucimannose Man3GlcNAc2 N-glycan. N-acetyl-d-glucosamine removal was inhibited by two N-acetylglucosaminidase inhibitors. Terminal GlcNAc was not released from [Manα1,6(Manα1,3)Manα1,6] (GlcNAcβ1,2Manα1,3)Manβ1,4GlcNAcβ1,4GlcNAc-R nor from the GlcNAcβ1,2Manα1,6Manβ- arm. These findings indicate that GLY-13 plays an important role in the synthesis of N-glycans by C. elegans and that therefore the worm should prove to be a suitable model for the study of the role of GnT I in nematode development.

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A role for Rab5 in structuring the endoplasmic reticulum

The Journal of Cell Biology ◽

10.1083/jcb.200701139 ◽

2007 ◽

Vol 178 (1) ◽

pp. 43-56 ◽

Cited By ~ 128

Author(s):

Anjon Audhya ◽

Arshad Desai ◽

Karen Oegema

Keyword(s):

Endoplasmic Reticulum ◽

Caenorhabditis Elegans ◽

Nuclear Envelope ◽

Rab Gtpases ◽

C Elegans ◽

Rab Family ◽

Kinetics Of

The endoplasmic reticulum (ER) is a contiguous network of interconnected membrane sheets and tubules. The ER is differentiated into distinct domains, including the peripheral ER and nuclear envelope. Inhibition of two ER proteins, Rtn4a and DP1/NogoA, was previously shown to inhibit the formation of ER tubules in vitro. We show that the formation of ER tubules in vitro also requires a Rab family GTPase. Characterization of the 29 Caenorhabditis elegans Rab GTPases reveals that depletion of RAB-5 phenocopies the defects in peripheral ER structure that result from depletion of RET-1 and YOP-1, the C. elegans homologues of Rtn4a and DP1/NogoA. Perturbation of endocytosis by other means did not affect ER structure; the role of RAB-5 in ER morphology is thus independent of its well-studied requirement for endocytosis. RAB-5 and YOP-1/RET-1 also control the kinetics of nuclear envelope disassembly, which suggests an important role for the morphology of the peripheral ER in this process.

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DAF-18 is required for the age-dependent increase in DAF-16 activity in Caenorhabditis elegans

10.1101/2020.11.16.384529 ◽

2020 ◽

Author(s):

Kali Carrasco ◽

Matthew J. Youngman

Keyword(s):

Caenorhabditis Elegans ◽

Functional Characterization ◽

Growth Factor Signaling ◽

Dynamic Activity ◽

Post Translational Modifications ◽

C Elegans ◽

Regulatory Module ◽

Phospholipid Signaling ◽

Age Dependent ◽

Foxo Transcription Factors

ABSTRACTThe insulin/insulin-like growth factor signaling (IIS) pathway modulates growth, survival, and lifespan by regulating FOXO transcription factors. In Caenorhabditis elegans, IIS maintains DAF-16/FOXO in an inactive state unless animals are challenged by environmental stress. Recent evidence suggests that DAF-16 becomes activated as part of normal aging in C. elegans, yet the regulatory module responsible for this phenomenon is largely undefined. Embedded within IIS is phospholipid signaling in which PIP3 produced by the PI3 kinase AGE-1 is an upstream event in DAF-16 inhibition. Countering AGE-1 is DAF-18, an ortholog of human PTEN phosphatase that dephosphorylates PIP3. Although it is required for normal lifespan in C. elegans, functional characterization of DAF-18 has primarily focused on its roles during development in the germline and neurons. In this study we asked whether DAF-18 plays a role in the age-dependent activation of DAF-16, and specifically in DAF-16-mediated immunity. Our data show that DAF-18 is expressed in multiple tissues during adulthood. We found that DAF-18 contributes to host defense in adult animals by functioning in the neurons and intestine, likely working through DAF-16 which acts in those same tissues to confer immunity. Supporting this possibility, DAF-18 was required for increased DAF-16 transcriptional activity during aging. Post-translational modifications including ubiquitination and sumoylation appear to be required for the function of DAF-18 during aging in C. elegans, indicating that strategies to modulate PTEN activity are evolutionarily conserved. Our results establish an important role for DAF-18 later in life and imply that it is a critical component of a neuroendocrine signaling circuit that governs the dynamic activity of DAF-16.

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Levels of Acid Sphingomyelinase (ASM) in Caenorhabditis elegans in Microgravity

Gravitational and Space Research ◽

10.2478/gsr-2018-0003 ◽

2020 ◽

Vol 6 (1) ◽

pp. 27-36 ◽

Cited By ~ 1

Author(s):

Annabel K. Gravely ◽

Alice Vlasov ◽

Amy Freeman ◽

Kay Wu ◽

Nathaniel J. Szewczyk ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Muscle Atrophy ◽

Space Station ◽

Acid Sphingomyelinase ◽

Cross Sectional ◽

C Elegans ◽

Microgravity Conditions ◽

Spaceflight Experiments ◽

Als Patients

AbstractBoth Amyotrophic Lateral Sclerosis (ALS) patients and astronauts in spaceflight suffer from muscle atrophy. Previous research suggests that the enzyme acid sphingomyelinase (ASM) may be involved in the pathogenesis of ALS, but it is not known if ASM influences muscle atrophy in microgravity. In this study, Caenorhabditis elegans (C. elegans) were exposed to microgravity conditions on the International Space Station (ISS) within the confines of a Fluid Mixing Enclosure (FME). Return of the FME yielded 72,050 live nematodes, the first demonstration of C. elegans survival of space travel in an FME. After the nematodes returned to Earth, in much larger numbers than seen in previous FME experiments, the size and ASM expression levels in experimental worms were compared to control Earth-bound worms. C. elegans that returned from the ISS were larger in both length and cross-sectional area than the control worms, and they exhibited decreased expression of ASM-1 and ASM-2 proteins. Further research must be conducted to elucidate the role of ASM in muscle atrophy, as there were many limitations to this study. Understanding the role of ASM in muscle atrophy may lead to the discovery of novel targets for treatment of both ALS and muscle atrophy in microgravity. This study was a student led initiative and undertaken as a project within the Student Spaceflight Experiments Program (SSEP), under the auspices of the National Center for Earth and Space Science Education and the Arthur C. Clarke Institute for Space Education.

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