Publications by authors named "Matt Simon"

7 Publications

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The meiotic phosphatase GSP-2/PP1 promotes germline immortality and small RNA-mediated genome silencing.

PLoS Genet 2019 03 28;15(3):e1008004. Epub 2019 Mar 28.

Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, United States of America.

Germ cell immortality, or transgenerational maintenance of the germ line, could be promoted by mechanisms that could occur in either mitotic or meiotic germ cells. Here we report for the first time that the GSP-2 PP1/Glc7 phosphatase promotes germ cell immortality. Small RNA-induced genome silencing is known to promote germ cell immortality, and we identified a separation-of-function allele of C. elegans gsp-2 that is compromised for germ cell immortality and is also defective for small RNA-induced genome silencing and meiotic but not mitotic chromosome segregation. Previous work has shown that GSP-2 is recruited to meiotic chromosomes by LAB-1, which also promoted germ cell immortality. At the generation of sterility, gsp-2 and lab-1 mutant adults displayed germline degeneration, univalents, histone methylation and histone phosphorylation defects in oocytes, phenotypes that mirror those observed in sterile small RNA-mediated genome silencing mutants. Our data suggest that a meiosis-specific function of GSP-2 ties small RNA-mediated silencing of the epigenome to germ cell immortality. We also show that transgenerational epigenomic silencing at hemizygous genetic elements requires the GSP-2 phosphatase, suggesting a functional link to small RNAs. Given that LAB-1 localizes to the interface between homologous chromosomes during pachytene, we hypothesize that small localized discontinuities at this interface could promote genomic silencing in a manner that depends on small RNAs and the GSP-2 phosphatase.
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http://dx.doi.org/10.1371/journal.pgen.1008004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456222PMC
March 2019

Challenging Cognitive Construals: A Dynamic Alternative to Stable Misconceptions.

CBE Life Sci Educ 2018 06;17(2):ar34

Department of Education, Tufts University, Medford, MA 02155.

In biology education research, it has been common to model cognition in terms of relatively stable knowledge structures (e.g., mental models, alternative frameworks, deeply held misconceptions). For example, John D. Coley and Kimberley D. Tanner recently proposed that many student difficulties in biology stem from underlying cognitive frameworks called cognitive construals ( CBE-Life Sciences Education, 11[3], 209-215 [2012]; CBE-Life Sciences Education, 14[1], ar8 [2015]). They argued that three such frameworks-teleology, anthropocentrism, and essentialism-cause undergraduate students to hold a range of misconceptions about the biological world. Our purpose in this article is to present an alternative perspective that considers student thinking to be dynamic and context sensitive. Using the example of cognitive construals, we argue that a dynamic perspective creates a burden of proof for claims of cognitive stability-to demonstrate that patterns of thinking are indeed stable across contexts. To illustrate our argument, we report on the results of a study designed to explore the stability of students' apparent teleological, anthropocentric, and essentialist thinking. Our results are inconsistent with framework models. We propose instead that response patterns stem from students' context-specific interpretations of the statements, consistent with dynamic models of cognition. Building on these preliminary findings, we discuss the implications of a dynamic view of cognition for biology education research and biology instruction.
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http://dx.doi.org/10.1187/cbe.17-10-0214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998328PMC
June 2018

Transgenerational Sterility of Piwi Mutants Represents a Dynamic Form of Adult Reproductive Diapause.

Cell Rep 2018 04;23(1):156-171

Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address:

Environmental stress can induce adult reproductive diapause, a state of developmental arrest that temporarily suspends reproduction. Deficiency for C. elegans Piwi protein PRG-1 results in strains that reproduce for many generations but then become sterile. We found that sterile-generation prg-1/Piwi mutants typically displayed pronounced germ cell atrophy as L4 larvae matured into 1-day-old adults. Atrophied germlines spontaneously reproliferated across the first days of adulthood, and this was accompanied by fertility for day 2-4 adults. Sterile day 5 prg-1 mutant adults remained sterile indefinitely, but providing an alternative food source could restore their fertility. Our data imply that late-generation prg-1 mutants experience a dynamic form of adult reproductive diapause, promoted by stress response, cell death, and RNAi pathways, where delayed fertility and reproductive quiescence represent parallel adaptive developmental outcomes. This may occur in response to a form of "heritable stress" that is transmitted by gametes and epigenetic in nature.
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http://dx.doi.org/10.1016/j.celrep.2018.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5918633PMC
April 2018

Caenorhabditis elegans RSD-2 and RSD-6 promote germ cell immortality by maintaining small interfering RNA populations.

Proc Natl Acad Sci U S A 2014 Oct 25;111(41):E4323-31. Epub 2014 Sep 25.

Departments of Genetics and Biology, Curriculum in Genetics and Molecular Biology, and

Germ cells are maintained in a pristine non-aging state as they proliferate over generations. Here, we show that a novel function of the Caenorhabditis elegans RNA interference proteins RNAi spreading defective (RSD)-2 and RSD-6 is to promote germ cell immortality at high temperature. rsd mutants cultured at high temperatures became progressively sterile and displayed loss of small interfering RNAs (siRNAs) that target spermatogenesis genes, simple repeats, and transposons. Desilencing of spermatogenesis genes occurred in late-generation rsd mutants, although defective spermatogenesis was insufficient to explain the majority of sterility. Increased expression of repetitive loci occurred in both germ and somatic cells of late-generation rsd mutant adults, suggesting that desilencing of many heterochromatic segments of the genome contributes to sterility. Nuclear RNAi defective (NRDE)-2 promotes nuclear silencing in response to exogenous double-stranded RNA, and our data imply that RSD-2, RSD-6, and NRDE-2 function in a common transgenerational nuclear silencing pathway that responds to endogenous siRNAs. We propose that RSD-2 and RSD-6 promote germ cell immortality at stressful temperatures by maintaining transgenerational epigenetic inheritance of endogenous siRNA populations that promote genome silencing.
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http://dx.doi.org/10.1073/pnas.1406131111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4205660PMC
October 2014

Reduced insulin/IGF-1 signaling restores germ cell immortality to Caenorhabditis elegans Piwi mutants.

Cell Rep 2014 May 24;7(3):762-73. Epub 2014 Apr 24.

Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address:

Defects in the Piwi/piRNA pathway lead to transposon desilencing and immediate sterility in many organisms. We found that the C. elegans Piwi mutant prg-1 became sterile after growth for many generations. This phenotype did not occur for RNAi mutants with strong transposon-silencing defects and was separable from the role of PRG-1 in transgene silencing. Brief periods of starvation extended the transgenerational lifespan of prg-1 mutants by stimulating the DAF-16/FOXO longevity transcription factor. Constitutive activation of DAF-16 via reduced daf-2 insulin/IGF-1 signaling immortalized prg-1 strains via RNAi proteins and histone H3 lysine 4 demethylases. In late-generation prg-1 mutants, desilencing of repetitive segments of the genome occurred, and silencing of repetitive loci was restored in prg-1; daf-2 mutants. This study reveals an unexpected interface between aging and transgenerational maintenance of germ cells, where somatic longevity is coupled to a genome-silencing pathway that promotes germ cell immortality in parallel to the Piwi/piRNA system.
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http://dx.doi.org/10.1016/j.celrep.2014.03.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049074PMC
May 2014

Caenorhabditis elegans POT-1 and POT-2 repress telomere maintenance pathways.

G3 (Bethesda) 2013 Feb 1;3(2):305-13. Epub 2013 Feb 1.

Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599-3280, USA.

Telomeres are composed of simple tandem DNA repeats that protect the ends of linear chromosomes from replicative erosion or inappropriate DNA damage response mechanisms. The mammalian Protection Of Telomeres (POT1) protein interacts with single-stranded telomeric DNA and can exert positive and negative effects on telomere length. Of four distinct POT1 homologs in the roundworm Caenorhabditis elegans, deficiency for POT-1 or POT-2 resulted in progressive telomere elongation that occurred because both proteins negatively regulate telomerase. We created a POT-1::mCherry fusion protein that forms discrete foci at C. elegans telomeres, independent of POT-2, allowing for live analysis of telomere dynamics. Transgenic pot-1::mCherry repressed telomerase in pot-1 mutants. Animals deficient for pot-1, but not pot-2, displayed mildly enhanced telomere erosion rates in the absence of the telomerase reverse transcriptase, trt-1. However, trt-1; pot-1 double mutants exhibited delayed senescence in comparison to trt-1 animals, and senescence was further delayed in trt-1; pot-2; pot-1 triple mutants, some of which survived robustly in the absence of telomerase. Our results indicate that POT-1 and POT-2 play independent roles in suppressing a telomerase-independent telomere maintenance pathway but may function together to repress telomerase.
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http://dx.doi.org/10.1534/g3.112.004440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564990PMC
February 2013

Clinical and laboratory characteristics of Clostridium difficile infection in patients with discordant diagnostic test results.

J Clin Microbiol 2012 Apr 11;50(4):1303-7. Epub 2012 Jan 11.

Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

The aim of this study was to compare the clinical and laboratory characteristics of Clostridium difficile infection (CDI) in patients with discordant test results for the cytotoxin assay (CYT) and PCR assays. A retrospective study from May to August 2008 and March to May 2010 was performed. CDI was diagnosed in 128 patients. PCR increased the yield of C. difficile cases by 2-fold compared to that of the CYT assay. Fifty-six cases (44%) were detected by PCR only (CYT negative). Forty-nine percent of patients with non-NAP1 strains were detected by PCR only, compared to 28% of those infected with NAP1 strains (P < 0.05). No significant differences were found in the clinical severity of illness and outcome among patients that tested positive for CDI by both tests (CYT and PCR) compared to those that tested positive by PCR only.
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http://dx.doi.org/10.1128/JCM.05711-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318505PMC
April 2012