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Juan I Fuxman Bass, Carles Pons, Lucie Kozlowski, John S Reece-Hoyes, Shaleen Shrestha, Amy D Holdorf, Akihiro Mori, Chad L Myers, Albertha Jm Walhout
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...
October 24, 2016: Molecular Systems Biology
Henk-Jan Westeneng, Renée Walhout, Milou Straathof, Ruben Schmidt, Jeroen Hendrikse, Jan H Veldink, Martijn P van den Heuvel, Leonard H van den Berg
BACKGROUND: In patients with a C9orf72 repeat expansion (C9+), a neuroimaging phenotype with widespread structural cerebral changes has been found. We aimed to investigate the specificity of this neuroimaging phenotype in patients with amyotrophic lateral sclerosis (ALS). METHODS: 156 C9- and 14 C9+ patients with ALS underwent high-resolution T1-weighted MRI; a subset (n=126) underwent diffusion-weighted imaging. Cortical thickness, subcortical volumes and white matter integrity were compared between C9+ and C9- patients...
October 18, 2016: Journal of Neurology, Neurosurgery, and Psychiatry
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 Jm Walhout
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...
2016: ELife
C J Walhout, A Acun, L Zhang, M Ezawa, H J W Zandvliet
The temperature dependence of the density of states of germanene, synthesized on Ge/Pt crystals, has been investigated with scanning tunneling spectroscopy. After correction for thermal broadening, a virtually perfect V-shaped density of states, which is a hallmark of a two-dimensional Dirac system, has been found. In an attempt to directly measure the energy dispersion relation via quasiparticle interference we have recorded spatial maps of the differential conductivity near the edges and defects of germanene...
July 20, 2016: Journal of Physics. Condensed Matter: An Institute of Physics Journal
L Safak Yilmaz, Albertha J M Walhout
Caenorhabditis elegans is a powerful model to study metabolism and how it relates to nutrition, gene expression, and life history traits. However, while numerous experimental techniques that enable perturbation of its diet and gene function are available, a high-quality metabolic network model has been lacking. Here, we reconstruct an initial version of the C. elegans metabolic network. This network model contains 1,273 genes, 623 enzymes, and 1,985 metabolic reactions and is referred to as iCEL1273. Using flux balance analysis, we show that iCEL1273 is capable of representing the conversion of bacterial biomass into C...
May 25, 2016: Cell Systems
Isaac G Alty, Douglas W Cheek, Tao Chen, David B Smith, Emma Q Walhout, Christopher J Abelt
The effects of intramolecular hydrogen-bonding on the fluorescence behavior of three derivatives of 6-propionyl-2-dimethylaminonaphthalene are reported. The H-bonding effects are revealed through comparisons with corresponding reference compounds in which the H-bond-donating hydroxyl groups are replaced with methoxy groups. In toluene, intramolecular H bonding gives rise to a dramatic increase in the fluorescence intensity but only a slight red shift in the position. This behavior is attributed to decreased efficiency in intersystem crossing due to an increase in the energy of the n → π* triplet state...
May 26, 2016: Journal of Physical Chemistry. A
Emma Watson, L Safak Yilmaz, Albertha J M Walhout
Metabolic networks are extensively regulated to facilitate tissue-specific metabolic programs and robustly maintain homeostasis in response to dietary changes. Homeostatic metabolic regulation is achieved through metabolite sensing coupled to feedback regulation of metabolic enzyme activity or expression. With a wealth of transcriptomic, proteomic, and metabolomic data available for different cell types across various conditions, we are challenged with understanding global metabolic network regulation and the resulting metabolic outputs...
2015: Annual Review of Genetics
Juan I Fuxman Bass, Nidhi Sahni, Shaleen Shrestha, Aurian Garcia-Gonzalez, Akihiro Mori, Numana Bhat, Song Yi, David E Hill, Marc Vidal, Albertha J M Walhout
Gene regulatory networks (GRNs) comprising interactions between transcription factors (TFs) and regulatory loci control development and physiology. Numerous disease-associated mutations have been identified, the vast majority residing in non-coding regions of the genome. As current GRN mapping methods test one TF at a time and require the use of cells harboring the mutation(s) of interest, they are not suitable to identify TFs that bind to wild-type and mutant loci. Here, we use gene-centered yeast one-hybrid (eY1H) assays to interrogate binding of 1,086 human TFs to 246 enhancers, as well as to 109 non-coding disease mutations...
April 23, 2015: Cell
Nidhi Sahni, Song Yi, Mikko Taipale, Juan I Fuxman Bass, Jasmin Coulombe-Huntington, Fan Yang, Jian Peng, Jochen Weile, Georgios I Karras, Yang Wang, István A Kovács, Atanas Kamburov, Irina Krykbaeva, Mandy H Lam, George Tucker, Vikram Khurana, Amitabh Sharma, Yang-Yu Liu, Nozomu Yachie, Quan Zhong, Yun Shen, Alexandre Palagi, Adriana San-Miguel, Changyu Fan, Dawit Balcha, Amelie Dricot, Daniel M Jordan, Jennifer M Walsh, Akash A Shah, Xinping Yang, Ani K Stoyanova, Alex Leighton, Michael A Calderwood, Yves Jacob, Michael E Cusick, Kourosh Salehi-Ashtiani, Luke J Whitesell, Shamil Sunyaev, Bonnie Berger, Albert-László Barabási, Benoit Charloteaux, David E Hill, Tong Hao, Frederick P Roth, Yu Xia, Albertha J M Walhout, Susan Lindquist, Marc Vidal
How disease-associated mutations impair protein activities in the context of biological networks remains mostly undetermined. Although a few renowned alleles are well characterized, functional information is missing for over 100,000 disease-associated variants. Here we functionally profile several thousand missense mutations across a spectrum of Mendelian disorders using various interaction assays. The majority of disease-associated alleles exhibit wild-type chaperone binding profiles, suggesting they preserve protein folding or stability...
April 23, 2015: Cell
Kamesh Narasimhan, Samuel A Lambert, Ally W H Yang, Jeremy Riddell, Sanie Mnaimneh, Hong Zheng, Mihai Albu, Hamed S Najafabadi, John S Reece-Hoyes, Juan I Fuxman Bass, Albertha J M Walhout, Matthew T Weirauch, Timothy R Hughes
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...
2015: ELife
Darryl Conte, Lesley T MacNeil, Albertha J M Walhout, Craig C Mello
RNAi has become an essential tool in C. elegans research. This unit describes procedures for RNAi in C. elegans by microinjecting with dsRNA, feeding with bacteria expressing dsRNA, and soaking in dsRNA solution, as well as high-throughput methods for RNAi-based screens.
2015: Current Protocols in Molecular Biology
Henk-Jan Westeneng, Esther Verstraete, Renée Walhout, Ruben Schmidt, Jeroen Hendrikse, Jan H Veldink, Martijn P van den Heuvel, Leonard H van den Berg
The aim of this study was to assess the involvement of deep gray matter, hippocampal subfields, and ventricular changes in patients with amyotrophic lateral sclerosis (ALS). A total of 112 ALS patients and 60 healthy subjects participated. High-resolution T1-weighted images were acquired using a 3T MRI scanner. Thirty-nine patients underwent a follow-up scan. Volumetric and shape analyses of subcortical structures were performed, measures were correlated with clinical parameters, and longitudinal changes were assessed...
February 2015: Neurobiology of Aging
Matthew T Weirauch, Ally Yang, Mihai Albu, Atina G Cote, Alejandro Montenegro-Montero, Philipp Drewe, Hamed S Najafabadi, Samuel A Lambert, Ishminder Mann, Kate Cook, Hong Zheng, Alejandra Goity, Harm van Bakel, Jean-Claude Lozano, Mary Galli, Mathew G Lewsey, Eryong Huang, Tuhin Mukherjee, Xiaoting Chen, John S Reece-Hoyes, Sridhar Govindarajan, Gad Shaulsky, Albertha J M Walhout, François-Yves Bouget, Gunnar Ratsch, Luis F Larrondo, Joseph R Ecker, Timothy R Hughes
Transcription factor (TF) DNA sequence preferences direct their regulatory activity, but are currently known for only ∼1% of eukaryotic TFs. Broadly sampling DNA-binding domain (DBD) types from multiple eukaryotic clades, we determined DNA sequence preferences for >1,000 TFs encompassing 54 different DBD classes from 131 diverse eukaryotes. We find that closely related DBDs almost always have very similar DNA sequence preferences, enabling inference of motifs for ∼34% of the ∼170,000 known or predicted eukaryotic TFs...
September 11, 2014: Cell
Lutfu Safak Yilmaz, Albertha J M Walhout
Micronutrients are required in small proportions in a diet to carry out key metabolic roles for biomass and energy production. Humans receive micronutrients either directly from their diet or from gut microbiota that metabolize other nutrients. The nematode Caenorhabditis elegans and its bacterial diet provide a relatively simple and genetically tractable model to study both direct and microbe-mediated effects of micronutrients. Recently, this model has been used to gain insight into the relationship between micronutrients, physiology, and metabolism...
November 2014: Trends in Genetics: TIG
Renée Walhout, Henk-Jan Westeneng, Esther Verstraete, Jeroen Hendrikse, Jan H Veldink, Martijn P van den Heuvel, Leonard H van den Berg
OBJECTIVE: Examine whether cortical thinning is a disease-specific phenomenon across the spectrum of motor neuron diseases in relation to upper motor neuron (UMN) involvement. METHODS: 153 patients (112 amyotrophic lateral sclerosis (ALS), 19 patients with a clinical UMN phenotype, 22 with a lower motor neuron (LMN) phenotype), 60 healthy controls and 43 patients with an ALS mimic disorder were included for a cross-sectional cortical thickness analysis. Thirty-nine patients with ALS underwent a follow-up scan...
March 2015: Journal of Neurology, Neurosurgery, and Psychiatry
Lesley T Macneil, Albertha Jm Walhout
C. elegans, both in the wild and in the lab, live on a diet of live bacteria. The bacterial diet provides nutrients for C. elegans, but can also play a number of other roles in C. elegans physiology. Recently, we compared the effects of different bacterial diets on life history traits and gene expression. Here, we discuss our recent findings in the context of other dietary studies and highlight challenges in understanding dietary effects. For instance, since bacteria can be pathogenic it can be difficult to disentangle pathogenic from dietary effects...
October 1, 2013: Worm
Emma Watson, Albertha J M Walhout
Diet greatly impacts metabolism in health and disease. In response to the presence or absence of specific nutrients, metabolic gene regulatory networks sense the metabolic state of the cell and regulate metabolic flux accordingly, for instance by the transcriptional control of metabolic enzymes. Here, we discuss recent insights regarding metazoan metabolic regulatory networks using the nematode Caenorhabditis elegans as a model, including the modular organization of metabolic gene regulatory networks, the prominent impact of diet on the transcriptome and metabolome, specialized roles of nuclear hormone receptors (NHRs) in responding to dietary conditions, regulation of metabolic genes and metabolic regulators by miRNAs, and feedback between metabolic genes and their regulators...
October 2014: Trends in Endocrinology and Metabolism: TEM
Emma Watson, Lesley T MacNeil, Ashlyn D Ritter, L Safak Yilmaz, Adam P Rosebrock, Amy A Caudy, Albertha J M Walhout
Diet greatly influences gene expression and physiology. In mammals, elucidating the effects and mechanisms of individual nutrients is challenging due to the complexity of both the animal and its diet. Here, we used an interspecies systems biology approach with Caenorhabditis elegans and two of its bacterial diets, Escherichia coli and Comamonas aquatica, to identify metabolites that affect the animal's gene expression and physiology. We identify vitamin B12 as the major dilutable metabolite provided by Comamonas aq...
February 13, 2014: Cell
Albertha J M Walhout
Diet affects cellular metabolism and organismal life history traits. Pang and Curran (2014) use Caenorhabditis elegans and its bacterial diets to unveil genetic perturbations in proline catabolism that shorten lifespan, but, only on specific Escherichia coli diets, thereby unveiling a genome-encoded adaptive response to different nutritional states.
February 4, 2014: Cell Metabolism
Juan I Fuxman Bass, Alos Diallo, Justin Nelson, Juan M Soto, Chad L Myers, Albertha J M Walhout
Biological networks can be used to functionally annotate genes on the basis of interaction-profile similarities. Metrics known as association indices can be used to quantify interaction-profile similarity. We provide an overview of commonly used association indices, including the Jaccard index and the Pearson correlation coefficient, and compare their performance in different types of analyses of biological networks. We introduce the Guide for Association Index for Networks (GAIN), a web tool for calculating and comparing interaction-profile similarities and defining modules of genes with similar profiles...
December 2013: Nature Methods
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