CaMK (CMK-1) and O-GlcNAc transferase (OGT-1) modulate mechanosensory responding and habituation in an interstimulus interval-dependent manner in<i>Caenorhabditis elegans</i>

El, Ardiel; Ta, McDiarmid; Ta, Timbers; Kcy, Lee; Safaei, Javad; Sl, Pelech; Ch, Rankin

doi:10.1101/115972

Cited by 5 publications

(7 citation statements)

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“…The O-GlcNAc modification is particularly abundant in the brain (25, 26), where it controls memory formation (27–29), circadian rhythm (30, 31), and appetite (32, 33). Numerous neuron-specific proteins are O-GlcNAcylated, such as the Microtubule-associated proteins tau (34) and CRMP2 (35), synaptic vesicle proteins (36), the transcriptional factor cyclic-AMP response element binding protein (CREB) (28), and the AMPA receptor GluA2 subunit (27).…”

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confidence: 99%

Catalytic deficiency of O-GlcNAc transferase leads to X-linked intellectual disability

Pravatà

Muha

Gundogdu

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

102

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O-GlcNAc transferase (OGT) is an X-linked gene product that is essential for normal development of the vertebrate embryo. It catalyses the O-GlcNAc posttranslational modification of nucleocytoplasmic proteins and proteolytic maturation of the transcriptional coregulator Host cell factor 1 (HCF1). Recent studies have suggested that conservative missense mutations distal to the OGT catalytic domain lead to X-linked intellectual disability in boys, but it is not clear if this is through changes in the O-GlcNAc proteome, loss of protein–protein interactions, or misprocessing of HCF1. Here, we report an OGT catalytic domain missense mutation in monozygotic female twins (c. X:70779215 T > A, p. N567K) with intellectual disability that allows dissection of these effects. The patients show limited IQ with developmental delay and skewed X-inactivation. Molecular analyses revealed decreased OGT stability and disruption of the substrate binding site, resulting in loss of catalytic activity. Editing this mutation into the Drosophila genome results in global changes in the O-GlcNAc proteome, while in mouse embryonic stem cells it leads to loss of O-GlcNAcase and delayed differentiation down the neuronal lineage. These data imply that catalytic deficiency of OGT could contribute to X-linked intellectual disability.

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confidence: 99%

Catalytic deficiency of O-GlcNAc transferase leads to X-linked intellectual disability

Pravatà

Muha

Gundogdu

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

102

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“…In the case of the taste cells in particular, calcium influx in response to the high sweetness of the diet together with higher GlcNAc levels due to the higher sugar concentration, could lead to the interaction of OGT with particular protein complexes, like PRC2, or its recruitment to specific loci. In contrast, different triggers and effector mechanisms could be at play when OGT modulates synapse maturation, neural excitability, and responses in other circuits and environmental or activity conditions 59,122–128 . Of note, neural activity is known to increase GlcNAc levels, suggesting that one of the functions of OGT is to prepare the cell to face metabolic and redox stress 47 .…”

Section: Discussionmentioning

confidence: 99%

Nutrigenomic Regulation of Sensory Plasticity

Vaziri

Wilinski

Freddolino

et al. 2021

Preprint

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Diet composition has a profound influence on brain physiology and behavior, but the mechanisms through which nutrient information is transmuted into neural changes remain elusive. Here we uncover how the metabolic enzyme O-GlcNAc Transferase (OGT) transforms information about the dietary environment into taste adaptations. We show that in the fly D. melanogaster, OGT decorates the chromatin of the sweet taste neurons and provides the nutrient context to drive changes in chromatin accessibility in response to high dietary sugar. Specifically, we found that OGT cooperates with the epigenetic silencer Polycomb Repressive Complex 2.1 (PRC2.1) to promote nutrient-sensitive variations in chromatin openness; these chromatin dynamics result in changes in gene expression and taste plasticity that are dependent on the catalytic activity of OGT. Parallel nutrigenomic signatures were also observed in the lingual epithelium of rats exposed to high dietary sugar, suggesting that this conserved metabolic-epigenetic pathway may also underlie diet-dependent taste changes in mammals. Together our findings reveal a novel role for nutriepigenetic signaling in the brain: amplifying nutrient perturbations into robust changes in chromatin accessibility and transcriptional output that shape neural and behavioral plasticity.

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“…can now be used in precision medicine drug screens aimed at identifying compounds that 402 counteract the affect of a particular patient's missense variant. Further broad-scale 403 phenomic characterization of targeted knockouts and mutant libraries combined with new 404 databases that curate ortholog functional annotation across model organisms should 405 expedite the process of in vivo functional assay development (Lee et al, 2018;406 McDiarmid et al, 2018;Thompson et al, 2013;Wang et al, 2017;Yemini et al, 2013). 407 408…”

Section: Combining Human Gene Replacement and Automated Phenomic Charmentioning

confidence: 99%

“…One of the goals of this resources article is to illustrate how Cas9-triggered 410 homologous recombination can be adapted to directly replace C. elegans genes with 411 human genes. An exciting adaptation of this approach will be to combine targeted human 412 gene insertions with bi-partite systems for precise spatial-temporal control of human 413 transgene expression, as has recently been done to overexpress human genes as UAS-414 20 cDNA constructs in Drosophila (Luo et al 2017;Lee et al 2018;Wangler et al 2017). 415…”

Section: Further Applications Of Targeted Human Gene Replacement 409mentioning

confidence: 99%

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CRISPR-Cas9 human gene replacement and phenomic characterization inCaenorhabditis elegansto understand the functional conservation of human genes and decipher variants of uncertain significance

McDiarmid

Loewen

et al. 2018

Preprint

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Our ability to sequence genomes has vastly surpassed our ability to interpret the genetic variation we discover. This presents a major challenge in the clinical setting, where the recent application of whole exome and whole genome sequencing has uncovered thousands of genetic variants of uncertain significance. Here, we present a strategy for targeted human gene replacement and phenomic characterization based on CRISPR-Cas9 genome engineering in the genetic model organism Caenorhabditis elegans that will facilitate assessment of the functional conservation of human genes and structure-function analysis of disease-associated variants with unprecedented precision.We validate our strategy by demonstrating that direct single-copy replacement of the C. elegans ortholog (daf-18) with the critical human disease-associated gene Phosphatase and Tensin Homolog (PTEN) is sufficient to rescue multiple phenotypic abnormalities caused by complete deletion of daf-18, including complex chemosensory and mechanosenory impairments. In addition, we used our strategy to generate animals harboring a single copy of the known pathogenic lipid phosphatase inactive PTEN variant (PTEN-G129E) and showed that our automated in vivo phenotypic assays could accurately and efficiently classify this missense variant as loss-of-function. The integrated nature of the human transgenes allows for analysis of both homozygous and heterozygous variants and greatly facilitates high-throughput precision medicine drug screens. By combining genome engineering with rapid and automated phenotypic characterization, our strategy streamlines identification of novel conserved gene functions in complex sensory and learning phenotypes that can be used as in vivo functional assays to decipher variants of uncertain significance. remarkably efficient and robust in C. elegans (Dickinson and Goldstein, 2016; Norris et 70 al., 2015). 71Here, we present a broadly applicable strategy that adapts CRISPR-Cas9 genome 72 engineering for targeted replacement of C. elegans genes with human genes. We illustrate 73 how the library of knockout and humanized transgenics generated with this approach can 74 be efficiently combined with automated machine vision phenotyping to rapidly discover 75 novel gene functions, assess the functional conservation of human genes, and how this 76 will allow for analysis of the effects of variants of uncertain significance with 77 unprecedented precision. It is our hope that the human gene replacement and phenomic 78 characterization strategy delineated in this article will serve both basic and health 79 researchers alike, by serving as an open and shareable resource that will aid any genome 80 engineer interested in understanding the functional conservation of human genes, and the 81 functional consequences of their variants. 82 83 Results 84A general genome editing strategy for direct replacement of a C. elegans gene with a 85 single copy of its human ortholog 86To replace the Open Reading Frame (ORF) of an orthologous gene with a human 87 gene ...

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CaMK (CMK-1) and O-GlcNAc transferase (OGT-1) modulate mechanosensory responding and habituation in an interstimulus interval-dependent manner inCaenorhabditis elegans

Abstract: (250 words)Many aspects of neural physiology, including processes that underlie learning (e. OGT-1 function in parallel pathways that may converge on a common substrate to modulate the tap processes present in all animals. peer-reviewed)

Cited by 5 publications

References 53 publications

Catalytic deficiency of O-GlcNAc transferase leads to X-linked intellectual disability

Catalytic deficiency of O-GlcNAc transferase leads to X-linked intellectual disability

Nutrigenomic Regulation of Sensory Plasticity

CRISPR-Cas9 human gene replacement and phenomic characterization inCaenorhabditis elegansto understand the functional conservation of human genes and decipher variants of uncertain significance

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