Kar4 is required for the normal pattern of meiotic gene expression
by Zachory M. Park, Matthew Remillard, Ethan Belnap, Mark D. Rose Kar4p, the yeast homolog of the mammalian methyltransferase subunit METTL14, is required for efficient mRNA m6A methylation, which regulates meiotic entry. Kar4p is also required for a second seemingly non-catalytic function during meiosis. Overexpression of the early meiotic transcription factor,IME1, can bypass the requirement for Kar4p in meiotic entry but the additional overexpression of the translational regulator,RIM4, is required to permit sporulation inkar4Δ/Δ. Using microarray analysis and RNA sequencing, we sought to determine the impact of remo...
Source: PLoS Genetics - August 28, 2023 Category: Genetics & Stem Cells Authors: Zachory M. Park Source Type: research

Genetic enhancers of partial PLK1 inhibition reveal hypersensitivity to kinetochore perturbations
by Karine Normandin, Jasmin Coulombe-Huntington, Corinne St-Denis, Alexandre Bernard, Mohammed Bourouh, Thierry Bertomeu, Mike Tyers, Vincent Archambault Polo-like kinase 1 (PLK1) is a serine/threonine kinase required for mitosis and cytokinesis. As cancer cells are often hypersensitive to partial PLK1 inactivation, chemical inhibitors of PLK1 have been developed and tested in clinical trials. However, these small molecule inhibitors alone are not completely effective. PLK1 promotes numerous molecular and cellular events in the cell division cycle and it is unclear which of these events most crucially depend on PLK1 activ...
Source: PLoS Genetics - August 28, 2023 Category: Genetics & Stem Cells Authors: Karine Normandin Source Type: research

MYC disrupts transcriptional and metabolic circadian oscillations in cancer and promotes enhanced biosynthesis
We report here that MYC disrupted over 85% of oscillating genes, while instead promoting enhanced ribosomal and mitochondrial biogenesis and suppressed cell attachment pathways. Notably, when MYC is activated, biosynthetic programs that were formerly circadian flipped to being upregulated in an oscillation-free manner. Further, activation of MYC ablates the oscillation of nutrient transporter proteins while greatly upregulating transporter expression, cell surface localization, and intracellular amino acid pools. Finally, we report that MYC disrupts metabolite oscillations and the temporal segregation of amino acid metabol...
Source: PLoS Genetics - August 28, 2023 Category: Genetics & Stem Cells Authors: Juliana Cazarin Source Type: research

β-Catenin transcriptional activity is required for establishment of inner pillar cell identity during cochlear development
by Michael Ebeid, Ippei Kishimoto, Pooja Roy, Mohd Ali Abbas Zaidi, Alan G. Cheng, Sung-Ho Huh The mammalian cochlea is composed of sensory hair cells as well as multiple different types of non-sensory supporting cells. Pillar cells are one type of supporting cell that form the tunnel of Corti and include two morphologically and functionally distinct subtypes: inner pillar cells (IPCs) and outer pillar cells (OPCs). The processes of specification and differentiation of inner versus outer pillar cells are still unclear. Here, we show that β-Catenin is required for establishing IPC identity in the mammalian cochlea. To dif...
Source: PLoS Genetics - August 28, 2023 Category: Genetics & Stem Cells Authors: Michael Ebeid Source Type: research

< i > Caenorhabditis elegans < /i > models for striated muscle disorders caused by missense variants of human < i > LMNA < /i >
by Ellen F. Gregory, Shilpi Kalra, Trisha Brock, Gis èle Bonne, G. W. Gant Luxton, Christopher Hopkins, Daniel A. Starr Striated muscle laminopathies caused by missense mutations in the nuclear lamin geneLMNA are characterized by cardiac dysfunction and often skeletal muscle defects. Attempts to predict whichLMNA variants are pathogenic and to understand their physiological effects lags behind variant discovery. We createdCaenorhabditis elegans models for striated muscle laminopathies by introducing pathogenic humanLMNA variants and variants of unknown significance at conserved residues within thelmn-1 gene. Severe misse...
Source: PLoS Genetics - August 25, 2023 Category: Genetics & Stem Cells Authors: Ellen F. Gregory Source Type: research

Localization of < i > oskar < /i > mRNA by agglomeration in ribonucleoprotein granules
by Catherine E. Eichler, Hui Li, Michelle E. Grunberg, Elizabeth R. Gavis Localization ofoskar mRNA to the posterior of theDrosophila oocyte is essential for abdominal patterning and germline development.oskar localization is a multi-step process involving temporally and mechanistically distinct transport modes. Numerous cis-acting elements and trans-acting factors have been identified that mediate earlier motor-dependent transport steps leading to an initial accumulation ofoskar at the posterior. Little is known, however, about the requirements for the later localization phase, which depends on cytoplasmic flows and resu...
Source: PLoS Genetics - August 25, 2023 Category: Genetics & Stem Cells Authors: Catherine E. Eichler Source Type: research

Artificial selection reveals complex genetic architecture of shoot branching and its response to nitrate supply in Arabidopsis
by Hugo Tavares, Anne Readshaw, Urszula Kania, Maaike de Jong, Raj K. Pasam, Hayley McCulloch, Sally Ward, Liron Shenhav, Elizabeth Forsyth, Ottoline Leyser Quantitative traits may be controlled by many loci, many alleles at each locus, and subject to genotype-by-environment interactions, making them difficult to map. One example of such a complex trait is shoot branching in the model plant Arabidopsis, and its plasticity in response to nitrate. Here, we use artificial selection under contrasting nitrate supplies to dissect the genetic architecture of this complex trait, where loci identified by association mapping failed...
Source: PLoS Genetics - August 24, 2023 Category: Genetics & Stem Cells Authors: Hugo Tavares Source Type: research

Neutrophil extracellular trap formation and gene programs distinguish TST/IGRA sensitization outcomes among < i > Mycobacterium tuberculosis < /i > exposed persons living with HIV
by Elouise E. Kroon, Wilian Correa-Macedo, Rachel Evans, Allison Seeger, Lize Engelbrecht, Jurgen A. Kriel, Ben Loos, Naomi Okugbeni, Marianna Orlova, Pauline Cassart, Craig J. Kinnear, Gerard C. Tromp, Marlo M öller, Robert J. Wilkinson, Anna K. Coussens, Erwin Schurr, Eileen G. Hoal Persons living with HIV (PLWH) have an increased risk for tuberculosis (TB). After prolonged and repeated exposure, some PLWH never develop TB and show no evidence of immune sensitization toMycobacterium tuberculosis (Mtb) as defined by persistently negative tuberculin skin tests (TST) and interferon gamma release assays (IGRA). This group ...
Source: PLoS Genetics - August 24, 2023 Category: Genetics & Stem Cells Authors: Elouise E. Kroon Source Type: research

Beyond a PPR-RNA recognition code: Many aspects matter for the multi-targeting properties of RNA editing factor PPR56
by Yingying Yang, Kira Ritzenhofen, Jessica Otrzonsek, Jingchan Xie, Mareike Schallenberg-R üdinger, Volker Knoop The mitochondrial C-to-U RNA editing factor PPR56 of the mossPhyscomitrium patens is an RNA-binding pentatricopeptide repeat protein equipped with a terminal DYW-type cytidine deaminase domain. Transferred intoEscherichia coli, PPR56 works faithfully on its two native RNA editing targets, nad3eU230SL and nad4eU272SL, and also converts cytidines into uridines at over 100 off-targets in the bacterial transcriptome. Accordingly, PPR56 is attractive for detailed mechanistic studies in the heterologous bacterial s...
Source: PLoS Genetics - August 21, 2023 Category: Genetics & Stem Cells Authors: Yingying Yang Source Type: research

Muscleblind-1 interacts with tubulin mRNAs to regulate the microtubule cytoskeleton in < i > C < /i > . < i > elegans < /i > mechanosensory neurons
by Dharmendra Puri, Sunanda Sharma, Sarbani Samaddar, Sruthy Ravivarma, Sourav Banerjee, Anindya Ghosh-Roy Regulation of the microtubule cytoskeleton is crucial for the development and maintenance of neuronal architecture, and recent studies have highlighted the significance of regulated RNA processing in the establishment and maintenance of neural circuits. In a genetic screen conducted using mechanosensory neurons ofC.elegans, we identified a mutation inmuscleblind-1/mbl-1 as a suppressor of loss of kinesin-13 family microtubule destabilizing factorklp-7. Muscleblind-1(MBL-1) is an RNA-binding protein that regulates the...
Source: PLoS Genetics - August 21, 2023 Category: Genetics & Stem Cells Authors: Dharmendra Puri Source Type: research

Kar4, the yeast homolog of METTL14, is required for mRNA m < sup > 6 < /sup > A methylation and meiosis
by Zachory M. Park, Abigail J. Sporer, Katherine Kraft, Krystal K. Lum, Edith Blackman, Ethan Belnap, Christopher M. Yellman, Mark D. RoseKAR4, the yeast homolog of the mammalian mRNA N6A-methyltransferase complex componentMETTL14, is required for two disparate developmental programs inSaccharomyces cerevisiae: mating and meiosis. To understandKAR4’s role in yeast mating and meiosis, we used a genetic screen to isolate 25 function-specific mutant alleles, which map to non-overlapping surfaces on a predicted structure of the Kar4 protein (Kar4p). Most of the mating-specific alleles (Mat-) abolish Kar4p ’s interaction wi...
Source: PLoS Genetics - August 21, 2023 Category: Genetics & Stem Cells Authors: Zachory M. Park Source Type: research

Regulation of chromatin accessibility and gene expression in the developing hippocampal primordium by LIM-HD transcription factor LHX2
We examined transcriptomic and chromatin-level features that distinguish the Hcp from the Ncp in the mouse during the early neurogenic period, embryonic day (E)12.5. ATAC-seq revealed that the Hcp was more accessible than the Ncp at this stage. Motif analysis of the differentially accessible loci in these tissues revealed LHX2 as a candidate transcription factor for modulating gene regulatory networks (GRNs). We analyzed LHX2 occupancy profiles and compared these with transcriptomic data from control andLhx2 mutant Hcp and Ncp at E12.5. Our results revealed that LHX2 directly regulates distinct genes in the Hcp and Ncp wit...
Source: PLoS Genetics - August 18, 2023 Category: Genetics & Stem Cells Authors: Varun Suresh Source Type: research

Multi-ancestry GWAS analysis identifies two novel loci associated with diabetic eye disease and highlights < i > APOL1 < /i > as a high risk locus in patients with diabetic macular edema
by Amy D. Stockwell, Michael C. Chang, Anubha Mahajan, William Forrest, Neha Anegondi, Rion K. Pendergrass, Suresh Selvaraj, Jens Reeder, Eric Wei, VA Iglesias, Natalie M. Creps, Laura Macri, Andrea N. Neeranjan, Marcel P. van der Brug, Suzie J. Scales, Mark I. McCarthy, Brian L. Yaspan Diabetic retinopathy (DR) is a common complication of diabetes. Approximately 20% of DR patients have diabetic macular edema (DME) characterized by fluid leakage into the retina. There is a genetic component to DR and DME risk, but few replicable loci. Because not all DR cases have DME, we focused on DME to increase power, and conducted a ...
Source: PLoS Genetics - August 16, 2023 Category: Genetics & Stem Cells Authors: Amy D. Stockwell Source Type: research

Functional mapping of N-terminal residues in the yeast proteome uncovers novel determinants for mitochondrial protein import
by Salom é Nashed, Houssam El Barbry, Médine Benchouaia, Angélie Dijoux-Maréchal, Thierry Delaveau, Nadia Ruiz-Gutierrez, Lucie Gaulier, Déborah Tribouillard-Tanvier, Guillaume Chevreux, Stéphane Le Crom, Benoit Palancade, Frédéric Devaux, Elodie Laine, Mathilde Garcia N-terminal ends of polypeptides are critical for the selective co-translational recruitment of N-terminal modification enzymes. However, it is unknown whether specific N-terminal signatures differentially regulate protein fate according to their cellular functions. In this work, we developed anin-silico approach to detect functional preferences in c...
Source: PLoS Genetics - August 16, 2023 Category: Genetics & Stem Cells Authors: Salom é Nashed Source Type: research

Accurate detection of shared genetic architecture from GWAS summary statistics in the small-sample context
by Thomas W. Willis, Chris Wallace Assessment of the genetic similarity between two phenotypes can provide insight into a common genetic aetiology and inform the use of pleiotropy-informed, cross-phenotype analytical methods to identify novel genetic associations. The genetic correlation is a well-known means of quantifying and testing for genetic similarity between traits, but its estimates are subject to comparatively large sampling error. This makes it unsuitable for use in a small-sample context. We discuss the use of a previously published nonparametric test of genetic similarity for application to GWAS summary stati...
Source: PLoS Genetics - August 16, 2023 Category: Genetics & Stem Cells Authors: Thomas W. Willis Source Type: research