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Full-Text Articles in Life Sciences

The Pseudomonas Aeruginosa Accessory Genome Elements Influence Virulence Towards Caenorhabditis Elegans, Alejandro Vasquez-Rifo, Isana Veksler-Lublinsky, Zhenyu Cheng, Frederick M. Ausubel, Victor R. Ambros Dec 2019

The Pseudomonas Aeruginosa Accessory Genome Elements Influence Virulence Towards Caenorhabditis Elegans, Alejandro Vasquez-Rifo, Isana Veksler-Lublinsky, Zhenyu Cheng, Frederick M. Ausubel, Victor R. Ambros

Open Access Articles

BACKGROUND: Multicellular animals and bacteria frequently engage in predator-prey and host-pathogen interactions, such as the well-studied relationship between Pseudomonas aeruginosa and the nematode Caenorhabditis elegans. This study investigates the genomic and genetic basis of bacterial-driven variability in P. aeruginosa virulence towards C. elegans to provide evolutionary insights into host-pathogen relationships.

RESULTS: Natural isolates of P. aeruginosa that exhibit diverse genomes display a broad range of virulence towards C. elegans. Using gene association and genetic analysis, we identify accessory genome elements that correlate with virulence, including both known and novel virulence determinants. Among the novel genes, we find a viral-like mobile ...


Redirection Of Skn-1 Abates The Negative Metabolic Outcomes Of A Perceived Pathogen Infection, James D. Nhan, Christian D. Turner, Sarah M. Anderson, Chia-An Yen, Hans M. Dalton, Hilary K. Cheesman, Dana L. Ruter, Nandhitha Uma Naresh, Cole M. Haynes, Alexander A. Soukas, Read Pukkila-Worley, Sean P. Curran Oct 2019

Redirection Of Skn-1 Abates The Negative Metabolic Outcomes Of A Perceived Pathogen Infection, James D. Nhan, Christian D. Turner, Sarah M. Anderson, Chia-An Yen, Hans M. Dalton, Hilary K. Cheesman, Dana L. Ruter, Nandhitha Uma Naresh, Cole M. Haynes, Alexander A. Soukas, Read Pukkila-Worley, Sean P. Curran

Open Access Articles

Early host responses toward pathogens are essential for defense against infection. In Caenorhabditis elegans, the transcription factor, SKN-1, regulates cellular defenses during xenobiotic intoxication and bacterial infection. However, constitutive activation of SKN-1 results in pleiotropic outcomes, including a redistribution of somatic lipids to the germline, which impairs health and shortens lifespan. Here, we show that exposing C. elegans to Pseudomonas aeruginosa similarly drives the rapid depletion of somatic, but not germline, lipid stores. Modulating the epigenetic landscape refines SKN-1 activity away from innate immunity targets, which alleviates negative metabolic outcomes. Similarly, exposure to oxidative stress redirects SKN-1 activity away from ...


Integrins Have Cell-Type-Specific Roles In The Development Of Motor Neuron Connectivity, Devyn Oliver, Emily Norman, Heather Bates, Rachel Avard, Monika Rettler, Claire Y. Benard, Michael M. Francis, Michele L. Lemons Aug 2019

Integrins Have Cell-Type-Specific Roles In The Development Of Motor Neuron Connectivity, Devyn Oliver, Emily Norman, Heather Bates, Rachel Avard, Monika Rettler, Claire Y. Benard, Michael M. Francis, Michele L. Lemons

Open Access Articles

Formation of the nervous system requires a complex series of events including proper extension and guidance of neuronal axons and dendrites. Here we investigate the requirement for integrins, a class of transmembrane cell adhesion receptors, in regulating these processes across classes of C. elegans motor neurons. We show alpha integrin/ina-1 is expressed by both GABAergic and cholinergic motor neurons. Despite this, our analysis of hypomorphic ina-1(gm144) mutants indicates preferential involvement of alpha integrin/ina-1 in GABAergic commissural development, without obvious involvement in cholinergic commissural development. The defects in GABAergic commissures of ina-1(gm144) mutants included both premature termination ...


Gain-Of-Function Mutations In The Unc-2/Cav2alpha Channel Lead To Excitation-Dominant Synaptic Transmission In C. Elegans, Yung-Chi Huang, Jennifer K. Pirri, Diego Rayes, Shangbang Gao, Ben Mulcahy, Jeff Grant, Yasunori Saheki, Michael M. Francis, Mei Zhen, Mark J. Alkema Aug 2019

Gain-Of-Function Mutations In The Unc-2/Cav2alpha Channel Lead To Excitation-Dominant Synaptic Transmission In C. Elegans, Yung-Chi Huang, Jennifer K. Pirri, Diego Rayes, Shangbang Gao, Ben Mulcahy, Jeff Grant, Yasunori Saheki, Michael M. Francis, Mei Zhen, Mark J. Alkema

Neurobiology Publications

Mutations in pre-synaptic voltage gated calcium channels can lead to familial hemiplegic migraine type 1 (FHM1). While mammalian studies indicate that the migraine brain is hyperexcitable due to enhanced excitation or reduced inhibition, the molecular and cellular mechanisms underlying this excitatory/inhibitory (E/I) imbalance are poorly understood. We identified a gain-of-function (gf) mutation in the Caenorhabditis elegans CaV2 channel alpha1 subunit, UNC-2, which leads to increased calcium currents. unc-2(zf35gf) mutants exhibit hyperactivity and seizure-like motor behaviors. Expression of the unc-2 gene with FHM1 substitutions R192Q and S218L leads to hyperactivity similar to that of unc-2(zf35gf) mutants. unc-2 ...


A Persistence Detector For Metabolic Network Rewiring In An Animal, Jote T. Bulcha, Gabrielle E. Giese, Zulfikar Ali, Yong-Uk Lee, Melissa D. Walker, Amy D. Holdorf, L. Safak Yilmaz, Robert C. Brewster, Albertha J. M. Walhout Jan 2019

A Persistence Detector For Metabolic Network Rewiring In An Animal, Jote T. Bulcha, Gabrielle E. Giese, Zulfikar Ali, Yong-Uk Lee, Melissa D. Walker, Amy D. Holdorf, L. Safak Yilmaz, Robert C. Brewster, Albertha J. M. Walhout

Open Access Articles

Biological systems must possess mechanisms that prevent inappropriate responses to spurious environmental inputs. Caenorhabditis elegans has two breakdown pathways for the short-chain fatty acid propionate: a canonical, vitamin B12-dependent pathway and a propionate shunt that is used when vitamin B12 levels are low. The shunt pathway is kept off when there is sufficient flux through the canonical pathway, likely to avoid generating shunt-specific toxic intermediates. Here, we discovered a transcriptional regulatory circuit that activates shunt gene expression upon propionate buildup. Nuclear hormone receptor 10 (NHR-10) and NHR-68 function together as a "persistence detector" in a type 1, coherent feed-forward loop ...


The Trim-Nhl Protein Nhl-2 Is A Co-Factor In The Nuclear And Somatic Rnai Pathways In C. Elegans, Gregory M. Davis, Shikui Tu, Jacqueline A. Wilce, Julie M. Claycomb, Zhiping Weng, Peter R. Boag Dec 2018

The Trim-Nhl Protein Nhl-2 Is A Co-Factor In The Nuclear And Somatic Rnai Pathways In C. Elegans, Gregory M. Davis, Shikui Tu, Jacqueline A. Wilce, Julie M. Claycomb, Zhiping Weng, Peter R. Boag

Program in Bioinformatics and Integrative Biology Publications

Proper regulation of germline gene expression is essential for fertility and maintaining species integrity. In the C. elegans germline, a diverse repertoire of regulatory pathways promote the expression of endogenous germline genes and limit the expression of deleterious transcripts to maintain genome homeostasis. Here we show that the conserved TRIM-NHL protein, NHL-2, plays an essential role in the C. elegans germline, modulating germline chromatin and meiotic chromosome organization. We uncover a role for NHL-2 as a co-factor in both positively (CSR-1) and negatively (HRDE-1) acting germline 22G-small RNA pathways and the somatic nuclear RNAi pathway. Furthermore, we demonstrate that NHL-2 ...


The Caenorhabditis Elegans Oxidative Stress Response Requires The Nhr-49 Transcription Factor, Queenie Hu, Dayana R. D'Amora, Lesley T. Macneil, Albertha J. M. Walhout, Terrance J. Kubiseski Dec 2018

The Caenorhabditis Elegans Oxidative Stress Response Requires The Nhr-49 Transcription Factor, Queenie Hu, Dayana R. D'Amora, Lesley T. Macneil, Albertha J. M. Walhout, Terrance J. Kubiseski

Open Access Articles

The overproduction of reactive oxygen species (ROS) in cells can lead to the development of diseases associated with aging. We have previously shown that C. elegans BRAP-2 (Brca1 associated binding protein 2) regulates phase II detoxification genes such as gst-4, by increasing SKN-1 activity. Previously, a transcription factor (TF) RNAi screen was conducted to identify potential activators that are required to induce gst-4 expression in brap-2(ok1492) mutants. The lipid metabolism regulator NHR-49/HNF4 was among 18 TFs identified. Here, we show that knockdown of nhr-49 suppresses the activation of gst-4 caused by brap-2 inactivation and that gain-of-function alleles of ...


Investigation Of Lin-28 Function In Somatic Gonadal Development And Fertility, And Characterization Of The Lin-28 Isoforms In C. Elegans Hermaphrodites, Sungwook Choi Aug 2018

Investigation Of Lin-28 Function In Somatic Gonadal Development And Fertility, And Characterization Of The Lin-28 Isoforms In C. Elegans Hermaphrodites, Sungwook Choi

GSBS Dissertations and Theses

lin-28 was first characterized as a developmental timing regulator in Caenorhabditis elegans. Loss of lin-28 function (lin-28(lf)) mutants skip the hypodermal cell fates specific to the 2nd larval stage. Here, we studied two aspects of lin-28 which had not yet been investigated.

First, we show that lin-28(lf) mutants exhibit reduced fertility associated with abnormal somatic gonadal morphology. In particular, the abnormal spermatheca-uterine valve morphology of lin-28(lf) hermaphrodites traps embryos in the spermatheca, which disrupts ovulation and causes embryonic lethality. The same genes downstream of lin-28 in the regulation of hypodermal developmental timing also act downstream of ...


A Persistence Detector For Metabolic Network Rewiring In An Animal, Jote T. Bulcha, Gabrielle E. Giese, Zulfikar Ali, Yong-Uk Lee, Melissa D. Walker, Amy D. Holdorf, L. Safak Yilmaz, Robert C. Brewster, Albertha J. M. Walhout Aug 2018

A Persistence Detector For Metabolic Network Rewiring In An Animal, Jote T. Bulcha, Gabrielle E. Giese, Zulfikar Ali, Yong-Uk Lee, Melissa D. Walker, Amy D. Holdorf, L. Safak Yilmaz, Robert C. Brewster, Albertha J. M. Walhout

University of Massachusetts Medical School Faculty Publications

Persistence detection is a mechanism that ensures a physiological output is only executed when the relevant input is sustained. Gene regulatory network circuits known as coherent type 1 feed forward loops (FFLs) with an AND-logic gate have been proposed to generate persistence detection. In such circuits two transcription factors (TFs) are both required to activate target genes and one of the two TFs activates the other. While numerous FFLs have been identified, examples of actual persistence detectors have only been described for bacteria. Here, we discover a transcriptional persistence detector in Caenorhabditis elegans involving the nuclear hormone receptors nhr-10 and ...


Neurexin Directs Partner-Specific Synaptic Connectivity In C. Elegans, Alison Philbrook, Shankar Ramachandran, Christopher M. Lambert, Devyn Oliver, Jeremy Florman, Mark J. Alkema, Michele Lemons, Michael M. Francis Jul 2018

Neurexin Directs Partner-Specific Synaptic Connectivity In C. Elegans, Alison Philbrook, Shankar Ramachandran, Christopher M. Lambert, Devyn Oliver, Jeremy Florman, Mark J. Alkema, Michele Lemons, Michael M. Francis

Open Access Articles

In neural circuits, individual neurons often make projections onto multiple postsynaptic partners. Here, we investigate molecular mechanisms by which these divergent connections are generated, using dyadic synapses in C. elegans as a model. We report that C. elegans nrx-1/neurexin directs divergent connectivity through differential actions at synapses with partnering neurons and muscles. We show that cholinergic outputs onto neurons are, unexpectedly, located at previously undefined spine-like protrusions from GABAergic dendrites. Both these spine-like features and cholinergic receptor clustering are strikingly disrupted in the absence of nrx-1. Excitatory transmission onto GABAergic neurons, but not neuromuscular transmission, is also disrupted. Our ...


Pie-1, Sumoylation, And Epigenetic Regulation Of Germline Specification In Caenorhabditis Elegans, Heesun Kim Jul 2018

Pie-1, Sumoylation, And Epigenetic Regulation Of Germline Specification In Caenorhabditis Elegans, Heesun Kim

GSBS Dissertations and Theses

In many organisms, the most fundamental event during embryogenesis is differentiating between germline cells and specialized somatic cells. In C. elegans, PIE-1 functions to protect the germline from somatic differentiation and appears to do so by blocking transcription and by preventing chromatin remodeling in the germline during early embryogenesis. Yet the molecular mechanisms by which PIE-1 specifies germline remain poorly understood. Our work shows that SUMOylation facilitates PIE-1-dependent germline maintenance and specification. In vivo SUMO purification in various CRISPR strains revealed that PIE-1 is SUMOylated at lysine 68 in the germline and that this SUMOylation is essential for forming NuRD ...


Effects Of Larval Density On Gene Regulation In C. Elegans During Routine L1 Synchronization, Oliver J. Rando, Io Long Chan, Colin C. Conine Mar 2018

Effects Of Larval Density On Gene Regulation In C. Elegans During Routine L1 Synchronization, Oliver J. Rando, Io Long Chan, Colin C. Conine

University of Massachusetts Medical School Faculty Publications

Bleaching gravid C. elegans followed by a short period of starvation of the L1 larvae is a routine method performed by worm researchers for generating synchronous populations for experiments. During the process of investigating dietary effects on gene regulation in L1 stage worms by single-worm RNA-Seq, we found that the density of resuspended L1 larvae affects expression of many mRNAs. Specifically, a number of genes related to metabolism and signalling are highly expressed in worms arrested at low density, but are repressed at higher arrest densities. We generated a GFP reporter strain based on one of the most density-dependent genes ...


Molecular Mechanisms Underlying Synaptic Connectivity In C. Elegans, Alison M. Philbrook Mar 2018

Molecular Mechanisms Underlying Synaptic Connectivity In C. Elegans, Alison M. Philbrook

GSBS Dissertations and Theses

Proper synaptic connectivity is critical for communication between cells and information processing in the brain. Neurons are highly interconnected, forming synapses with multiple partners, and these connections are often refined during the course of development. While decades of research have elucidated many molecular players that regulate these processes, understanding their specific roles can be difficult due to the large number of synapses and complex circuitry in the brain. In this thesis, I investigate mechanisms that establish neural circuits in the simple organism C. elegans, allowing us to address this important problem with single cell resolution in vivo.

First, I investigate ...


The Coding Regions Of Germline Mrnas Confer Sensitivity To Argonaute Regulation In C. Elegans, Meetu Seth, Masaki Shirayama, Wen Tang, En-Zhi Shen, Shikui Tu, Heng-Chi Lee, Zhiping Weng, Craig C. Mello Feb 2018

The Coding Regions Of Germline Mrnas Confer Sensitivity To Argonaute Regulation In C. Elegans, Meetu Seth, Masaki Shirayama, Wen Tang, En-Zhi Shen, Shikui Tu, Heng-Chi Lee, Zhiping Weng, Craig C. Mello

RNA Therapeutics Institute Publications

Protein-coding genes undergo a wide array of regulatory interactions with factors that engage non-coding regions. Open reading frames (ORFs), in contrast, are thought to be constrained by coding function, precluding a major role in gene regulation. Here, we explore Piwi-interacting (pi)RNA-mediated transgene silencing in C. elegans and show that marked differences in the sensitivity to piRNA silencing map to the endogenous sequences within transgene ORFs. Artificially increasing piRNA targeting within the ORF of a resistant transgene can lead to a partial yet stable reduction in expression, revealing that piRNAs not only silence but can also "tune" gene expression. Our ...


Excitatory Motor Neurons Are Local Oscillators For Backward Locomotion, Shangbang Gao, Sihui Asuka Guan, Anthony D. Fouad, Jun Meng, Taizo Kawano, Yung-Chi Huang, Yi Li, Salvador Alcaire, Wesley Hung, Yangning Lu, Yingchuan Billy Qi, Yishi Jin, Mark J. Alkema, Christopher Fang-Yen, Mei Zhen Jan 2018

Excitatory Motor Neurons Are Local Oscillators For Backward Locomotion, Shangbang Gao, Sihui Asuka Guan, Anthony D. Fouad, Jun Meng, Taizo Kawano, Yung-Chi Huang, Yi Li, Salvador Alcaire, Wesley Hung, Yangning Lu, Yingchuan Billy Qi, Yishi Jin, Mark J. Alkema, Christopher Fang-Yen, Mei Zhen

Open Access Articles

Cell- or network-driven oscillators underlie motor rhythmicity. The identity of C. elegans oscillators remains unknown. Through cell ablation, electrophysiology, and calcium imaging, we show: (1) forward and backward locomotion is driven by different oscillators; (2) the cholinergic and excitatory A-class motor neurons exhibit intrinsic and oscillatory activity that is sufficient to drive backward locomotion in the absence of premotor interneurons; (3) the UNC-2 P/Q/N high-voltage-activated calcium current underlies A motor neuron's oscillation; (4) descending premotor interneurons AVA, via an evolutionarily conserved, mixed gap junction and chemical synapse configuration, exert state-dependent inhibition and potentiation of A motor neuron ...


C. Elegans Multidrug Resistance Protein 5 (Mrp-5) Transports Vitamin B12 From The Intestine To The Gonad To Support Embryonic Development, Huimin Na, Olga Ponomarova, Gabrielle E. Giese, Albertha J. M. Walhout Jan 2018

C. Elegans Multidrug Resistance Protein 5 (Mrp-5) Transports Vitamin B12 From The Intestine To The Gonad To Support Embryonic Development, Huimin Na, Olga Ponomarova, Gabrielle E. Giese, Albertha J. M. Walhout

University of Massachusetts Medical School Faculty Publications

Vitamin B12 functions as a cofactor for methionine synthase to produce the anabolic methyl donor S-adenosylmethionine (SAM) and for methylmalonyl-CoA mutase to catabolize the short chain fatty acid propionate. In the nematode Caenorhabditis elegans, maternally supplied vitamin B12 is required for the development of her offspring. However, the mechanism for exporting vitamin B12 from the mother to her offspring is not yet known. Here, we use RNAi of more than 200 transporters with a vitamin B12-sensor transgene to identify the ABC transporter MRP-5 as a candidate vitamin B12 exporter. We show that injection of vitamin B12 into the gonad of ...


Sophisticated Lessons From Simple Organisms: Appreciating The Value Of Curiosity-Driven Research, Robert J. Duronio, Patrick H. O'Farrell, Greenfield Sluder, Tin Tin Su Dec 2017

Sophisticated Lessons From Simple Organisms: Appreciating The Value Of Curiosity-Driven Research, Robert J. Duronio, Patrick H. O'Farrell, Greenfield Sluder, Tin Tin Su

Radiology Publications

For hundreds of years, biologists have studied accessible organisms such as garden peas, sea urchins collected at low tide, newt eggs, and flies circling rotten fruit. These organisms help us to understand the world around us, attracting and inspiring each new generation of biologists with the promise of mystery and discovery. Time and time again, what we learn from such simple organisms has emphasized our common biological origins by proving to be applicable to more complex organisms, including humans. Yet, biologists are increasingly being tasked with developing applications from the known, rather than being allowed to follow a path to ...


Hlh-30/Tfeb-Mediated Autophagy Functions In A Cell-Autonomous Manner For Epithelium Intrinsic Cellular Defense Against Bacterial Pore-Forming Toxin In C. Elegans, Huan-Da Chen, Raffi V. Aroian, Chang-Shi Chen Feb 2017

Hlh-30/Tfeb-Mediated Autophagy Functions In A Cell-Autonomous Manner For Epithelium Intrinsic Cellular Defense Against Bacterial Pore-Forming Toxin In C. Elegans, Huan-Da Chen, Raffi V. Aroian, Chang-Shi Chen

Open Access Articles

Autophagy is an evolutionarily conserved intracellular system that maintains cellular homeostasis by degrading and recycling damaged cellular components. The transcription factor HLH-30/TFEB-mediated autophagy has been reported to regulate tolerance to bacterial infection, but less is known about the bona fide bacterial effector that activates HLH-30 and autophagy. Here, we reveal that bacterial membrane pore-forming toxin (PFT) induces autophagy in an HLH-30-dependent manner in Caenorhabditis elegans. Moreover, autophagy controls the susceptibility of animals to PFT toxicity through xenophagic degradation of PFT and repair of membrane-pore cell-autonomously in the PFT-targeted intestinal cells in C. elegans. These results demonstrate that autophagic pathways ...


Mirnas Cooperate In Apoptosis Regulation During C. Elegans Development, Ryan Sherrard, Sebastian Luehr, Heinke Holzkamp, Katherine Mcjunkin, Nadin Memar, Barbara Conradt Jan 2017

Mirnas Cooperate In Apoptosis Regulation During C. Elegans Development, Ryan Sherrard, Sebastian Luehr, Heinke Holzkamp, Katherine Mcjunkin, Nadin Memar, Barbara Conradt

Open Access Articles

Programmed cell death occurs in a highly reproducible manner during Caenorhabditis elegans development. We demonstrate that, during embryogenesis, miR-35 and miR-58 bantam family microRNAs (miRNAs) cooperate to prevent the precocious death of mothers of cells programmed to die by repressing the gene egl-1, which encodes a proapoptotic BH3-only protein. In addition, we present evidence that repression of egl-1 is dependent on binding sites for miR-35 and miR-58 family miRNAs within the egl-1 3' untranslated region (UTR), which affect both mRNA copy number and translation. Furthermore, using single-molecule RNA fluorescent in situ hybridization (smRNA FISH), we show that egl-1 is transcribed ...


Temporal Organization Of Behavioral States Through Local Neuromodulation In C. Elegans, Navonil Banerjee Dec 2016

Temporal Organization Of Behavioral States Through Local Neuromodulation In C. Elegans, Navonil Banerjee

GSBS Dissertations and Theses

Neuropeptide signaling play critical roles in maintaining distinct behavioral states and orchestrating transitions between them. However, elucidating the mechanisms underlying neuropeptide modulation of neural circuits in vivo remains a major challenge. The nematode Caenorhabditis elegans serves as an excellent model organism to study neuropeptide signaling mechanisms encoded in relatively simple neural circuits. We have used the C. elegans egg-laying circuit as a model to understand how neuropeptide signaling modifies circuit activity to generate opposing behavioral outcomes. C. elegans egg-laying behavior is composed of alternating cycles of two states – short bursts of egg deposition (active phases) and prolonged periods of quiescence ...


Circadian Rhythms Identified In Caenorhabditis Elegans By In Vivo Long-Term Monitoring Of A Bioluminescent Reporter, Maria Eugenia Goya, Andres Romanowski, Carlos S. Caldart, Claire Y. Benard, Diego A. Golombek Nov 2016

Circadian Rhythms Identified In Caenorhabditis Elegans By In Vivo Long-Term Monitoring Of A Bioluminescent Reporter, Maria Eugenia Goya, Andres Romanowski, Carlos S. Caldart, Claire Y. Benard, Diego A. Golombek

Neurobiology Publications

Circadian rhythms are based on endogenous clocks that allow organisms to adjust their physiology and behavior by entrainment to the solar day and, in turn, to select the optimal times for most biological variables. Diverse model systems-including mice, flies, fungi, plants, and bacteria-have provided important insights into the mechanisms of circadian rhythmicity. However, the general principles that govern the circadian clock of Caenorhabditis elegans have remained largely elusive. Here we report robust molecular circadian rhythms in C elegans recorded with a bioluminescence assay in vivo and demonstrate the main features of the circadian system of the nematode. By constructing a ...


A Gene-Centered C. Elegans Protein-Dna Interaction Network Provides A Framework For Functional Predictions, Juan Fuxman Bass, Carles Pons, Lucie Kozlowski, John S. Reece-Hoyes, Shaleen Shrestha, Amy D. Holdorf, Akihiro Mori, Chad L. Myers, Albertha J. M. Walhout Oct 2016

A Gene-Centered C. Elegans Protein-Dna Interaction Network Provides A Framework For Functional Predictions, Juan Fuxman Bass, Carles Pons, Lucie Kozlowski, John S. Reece-Hoyes, Shaleen Shrestha, Amy D. Holdorf, Akihiro Mori, Chad L. Myers, Albertha J. M. Walhout

Open Access Articles

Transcription factors (TFs) play a central role in controlling spatiotemporal gene expression and the response to environmental cues. A comprehensive understanding of gene regulation requires integrating physical protein-DNA interactions (PDIs) with TF regulatory activity, expression patterns, and phenotypic data. Although great progress has been made in mapping PDIs using chromatin immunoprecipitation, these studies have only characterized ~10% of TFs in any metazoan species. The nematode C. elegans has been widely used to study gene regulation due to its compact genome with short regulatory sequences. Here, we delineated the largest gene-centered metazoan PDI network to date by examining interactions between 90 ...


Metabolic Network Rewiring Of Propionate Flux Compensates Vitamin B12 Deficiency In C. Elegans, Emma Watson, Viridiana Olin-Sandoval, Michael J. Hoy, Chi-Hua Li, Timo Louisse, Victoria Yao, Akihiro Mori, Amy D. Holdorf, Olga G. Troyanskaya, Markus Ralser, Albertha J. M. Walhout Jul 2016

Metabolic Network Rewiring Of Propionate Flux Compensates Vitamin B12 Deficiency In C. Elegans, Emma Watson, Viridiana Olin-Sandoval, Michael J. Hoy, Chi-Hua Li, Timo Louisse, Victoria Yao, Akihiro Mori, Amy D. Holdorf, Olga G. Troyanskaya, Markus Ralser, Albertha J. M. Walhout

Open Access Articles

Metabolic network rewiring is the rerouting of metabolism through the use of alternate enzymes to adjust pathway flux and accomplish specific anabolic or catabolic objectives. Here, we report the first characterization of two parallel pathways for the breakdown of the short chain fatty acid propionate in Caenorhabditis elegans. Using genetic interaction mapping, gene co-expression analysis, pathway intermediate quantification and carbon tracing, we uncover a vitamin B12-independent propionate breakdown shunt that is transcriptionally activated on vitamin B12 deficient diets, or under genetic conditions mimicking the human diseases propionic- and methylmalonic acidemia, in which the canonical B12-dependent propionate breakdown pathway is blocked ...


Pan-Neuronal Imaging In Roaming Caenorhabditis Elegans, Vivek Venkatachalam, Ni Ji, Xian Wang, Christopher M. Clark, James Kameron Mitchell, Mason Klein, Christopher J. Tabone, Jeremy Florman, Hongfei Ji, Joel Greenwood, Andrew D. Chisholm, Jagan Srinivasan, Mark J. Alkema, Mei Zhen, Aravinthan D.T. Samuel Feb 2016

Pan-Neuronal Imaging In Roaming Caenorhabditis Elegans, Vivek Venkatachalam, Ni Ji, Xian Wang, Christopher M. Clark, James Kameron Mitchell, Mason Klein, Christopher J. Tabone, Jeremy Florman, Hongfei Ji, Joel Greenwood, Andrew D. Chisholm, Jagan Srinivasan, Mark J. Alkema, Mei Zhen, Aravinthan D.T. Samuel

GSBS Student Publications

We present an imaging system for pan-neuronal recording in crawling Caenorhabditis elegans. A spinning disk confocal microscope, modified for automated tracking of the C. elegans head ganglia, simultaneously records the activity and position of approximately 80 neurons that coexpress cytoplasmic calcium indicator GCaMP6s and nuclear localized red fluorescent protein at 10 volumes per second. We developed a behavioral analysis algorithm that maps the movements of the head ganglia to the animal's posture and locomotion. Image registration and analysis software automatically assigns an index to each nucleus and calculates the corresponding calcium signal. Neurons with highly stereotyped positions can be ...


Mapping And Analysis Of Caenorhabditis Elegans Transcription Factor Sequence Specificities, Kamesh Narasimhan, Samuel A. Lambert, Ally Yang, Jeremy Riddell, Sanie Mnaimneh, Hong Zheng, Mihai Albu, Hamed S. Najafabadi, John S. Reece-Hoyes, Juan Fuxman Bass, Albertha J. M. Walhout, Matthew T. Weirauch, Timothy R. Hughes Apr 2015

Mapping And Analysis Of Caenorhabditis Elegans Transcription Factor Sequence Specificities, Kamesh Narasimhan, Samuel A. Lambert, Ally Yang, Jeremy Riddell, Sanie Mnaimneh, Hong Zheng, Mihai Albu, Hamed S. Najafabadi, John S. Reece-Hoyes, Juan Fuxman Bass, Albertha J. M. Walhout, Matthew T. Weirauch, Timothy R. Hughes

Program in Systems Biology Publications

Caenorhabditis elegans is a powerful model for studying gene regulation, as it has a compact genome and a wealth of genomic tools. However, identification of regulatory elements has been limited, as DNA-binding motifs are known for only 71 of the estimated 763 sequence-specific transcription factors (TFs). To address this problem, we performed protein binding microarray experiments on representatives of canonical TF families in C. elegans, obtaining motifs for 129 TFs. Additionally, we predict motifs for many TFs that have DNA-binding domains similar to those already characterized, increasing coverage of binding specificities to 292 C. elegans TFs (~40%). These data highlight ...


Using C. Elegans For Aging Research, Heidi A. Tissenbaum Jan 2015

Using C. Elegans For Aging Research, Heidi A. Tissenbaum

Molecular, Cell and Cancer Biology Publications

Over a century ago, the zoologist Emile Maupas first identified the nematode, Rhabditis elegans, in the soil in Algiers. Subsequent work and phylogenic studies renamed the species Caenorhabditis elegans or more commonly referred to as C. elegans; (Caeno meaning recent; rhabditis meaning rod; elegans meaning nice). However, it was not until 1963, when Sydney Brenner, already successful from his work on DNA, RNA, and the genetic code, suggested the future of biological research lay in model organisms. Brenner believed that biological research required a model system that could grow in vast quantities in the lab, were cheap to maintain and ...


Multiple Transcription Factors Directly Regulate Hox Gene Lin-39 Expression In Ventral Hypodermal Cells Of The C. Elegans Embryo And Larva, Including The Hypodermal Fate Regulators Lin-26 And Elt-6, Wan-Ju Liu, John S. Reece-Hoyes, Albertha J. M. Walhout, David M. Eisenmann May 2014

Multiple Transcription Factors Directly Regulate Hox Gene Lin-39 Expression In Ventral Hypodermal Cells Of The C. Elegans Embryo And Larva, Including The Hypodermal Fate Regulators Lin-26 And Elt-6, Wan-Ju Liu, John S. Reece-Hoyes, Albertha J. M. Walhout, David M. Eisenmann

Program in Systems Biology Publications

BACKGROUND: Hox genes encode master regulators of regional fate specification during early metazoan development. Much is known about the initiation and regulation of Hox gene expression in Drosophila and vertebrates, but less is known in the non-arthropod invertebrate model system, C. elegans. The C. elegans Hox gene lin-39 is required for correct fate specification in the midbody region, including the Vulval Precursor Cells (VPCs). To better understand lin-39 regulation and function, we aimed to identify transcription factors necessary for lin-39 expression in the VPCs, and in particular sought factors that initiate lin-39 expression in the embryo.

RESULTS: We used the ...


Transcriptional Regulation Of Caenorhabditis Elegans Foxo/Daf-16 Modulates Lifespan, Ankita Bansal, Eun-Soo Kwon, Darryl Conte Jr., Haibo Liu, Michael J. Gilchrist, Lesley T. Macneil, Heidi A. Tissenbaum Apr 2014

Transcriptional Regulation Of Caenorhabditis Elegans Foxo/Daf-16 Modulates Lifespan, Ankita Bansal, Eun-Soo Kwon, Darryl Conte Jr., Haibo Liu, Michael J. Gilchrist, Lesley T. Macneil, Heidi A. Tissenbaum

Program in Gene Function and Expression Publications

BACKGROUND: Insulin/IGF-1 signaling plays a central role in longevity across phylogeny. In C. elegans, the forkhead box O (FOXO) transcription factor, DAF-16, is the primary target of insulin/IGF-1 signaling, and multiple isoforms of DAF-16 (a, b, and d/f) modulate lifespan, metabolism, dauer formation, and stress resistance. Thus far, across phylogeny modulation of mammalian FOXOs and DAF-16 have focused on post-translational regulation with little focus on transcriptional regulation. In C. elegans, we have previously shown that DAF-16d/f cooperates with DAF-16a to promote longevity. In this study, we generated transgenic strains expressing near-endogenous levels of either daf-16a or ...


Simultaneous Optogenetic Manipulation And Calcium Imaging In Freely Moving C. Elegans, Frederick B. Shipley, Christopher M. Clark, Mark J. Alkema, Andrew M. Leifer Apr 2014

Simultaneous Optogenetic Manipulation And Calcium Imaging In Freely Moving C. Elegans, Frederick B. Shipley, Christopher M. Clark, Mark J. Alkema, Andrew M. Leifer

University of Massachusetts Medical School Faculty Publications

A fundamental goal of systems neuroscience is to probe the dynamics of neural activity that drive behavior. Here we present an instrument to simultaneously manipulate neural activity via Channelrhodopsin, monitor neural response via GCaMP3, and observes behavior in freely moving C. elegans. We use the instrument to directly observe the relation between sensory stimuli, interneuron activity and locomotion in the mechanosensory circuit. Now published as: Front Neural Circuits 8:28, doi:10.3389/fncir.2014.00028


Intercellular Calcium Signaling In A Gap Junction-Coupled Cell Network Establishes Asymmetric Neuronal Fates In C. Elegans, Jennifer A. Schumacher, Yi-Wen Hsieh, Shiuhwei Chen, Jennifer K. Pirri, Mark J. Alkema, Wen-Hong Li, Chieh Chang, Chiou-Fen Chuang Nov 2012

Intercellular Calcium Signaling In A Gap Junction-Coupled Cell Network Establishes Asymmetric Neuronal Fates In C. Elegans, Jennifer A. Schumacher, Yi-Wen Hsieh, Shiuhwei Chen, Jennifer K. Pirri, Mark J. Alkema, Wen-Hong Li, Chieh Chang, Chiou-Fen Chuang

Neurobiology Publications

The C. elegans left and right AWC olfactory neurons specify asymmetric subtypes, one default AWC(OFF) and one induced AWC(ON), through a stochastic, coordinated cell signaling event. Intercellular communication between AWCs and non-AWC neurons via a NSY-5 gap junction network coordinates AWC asymmetry. However, the nature of intercellular signaling across the network and how individual non-AWC cells in the network influence AWC asymmetry is not known. Here, we demonstrate that intercellular calcium signaling through the NSY-5 gap junction neural network coordinates a precise 1AWC(ON)/1AWC(OFF) decision. We show that NSY-5 gap junctions in C. elegans cells mediate ...