500+ Papers found (0.012 seconds)

Xu W et al. (2011) Cancer Cell "Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases."

Wang P, Liu J, Xu YH, Yang H, Xu W, Liu LX, Zhao SM, Wang B, Kim SH, Xiao MT, Xiong Y, Zhang Y, Ito S, Frye S, Jiang WQ, Lei QY, Zhang JY, Guan KL, Liu Y, Yang C, Yang Y

[

Cancer Cell,

2011]

IDH1 and IDH2 mutations occur frequently in gliomas and acute myeloid leukemia, leading to simultaneous loss and gain of activities in the production of alpha-ketoglutarate (alpha-KG) and 2-hydroxyglutarate (2-HG), respectively. Here we demonstrate that 2-HG is a competitive inhibitor of multiple alpha-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases. 2-HG occupies the same space as alpha-KG does in the active site of histone demethylases. Ectopic expression of tumor-derived IDH1 and IDH2 mutants inhibits histone demethylation and 5mC hydroxylation. In glioma, IDH1 mutations are associated with increased histone methylation and decreased 5-hydroxylmethylcytosine (5hmC). Hence, tumor-derived IDH1 and IDH2 mutations reduce alpha-KG and accumulate an alpha-KG antagonist, 2-HG, leading to genome-wide histone and DNA methylation alterations.

Xu W et al. (2019) Elife "Evolution of Yin and Yang isoforms of a chromatin remodeling subunit precedes the creation of two genes."

Zhao Y, Stevens L, Munoz J, McGrath PT, Long L, Xu W, Felipe I, Ellis RE

[

Elife,

2019]

Genes can encode multiple isoforms, broadening their functions and providing a molecular substrate to evolve phenotypic diversity. Evolution of isoform function is a potential route to adapt to new environments. Here we show that de novo, beneficial alleles in the nurf-1 gene became fixed in two laboratory lineages of C. elegans after isolation from the wild in 1951, before methods of cryopreservation were developed. nurf-1 encodes an ortholog of BPTF, a large (>300kD) multidomain subunit of the NURF chromatin remodeling complex. Using CRISPR-Cas9 genome editing and transgenic rescue, we demonstrate that in C. elegans, nurf-1 has split into two, largely non-overlapping isoforms (NURF-1.D and NURF-1.B, which we call Yin and Yang, respectively) that share only two of 26 exons. Both isoforms are essential for normal gametogenesis but have opposite effects on male/female gamete differentiation. Reproduction in hermaphrodites, which involves production of both sperm and oocytes, requires a balance of these opposing Yin and Yang isoforms. Transgenic rescue and genetic position of the fixed mutations suggest that different isoforms are modified in each laboratory strain. In a related clade of Caenorhabditis nematodes, the shared exons have duplicated, resulting in the split of the Yin and Yang isoforms into separate genes, each containing approximately 200 amino acids of duplicated sequence that has undergone accelerated protein evolution following the duplication. Associated with this duplication event is the loss of two additional nurf-1 transcripts, including the long-form transcript and a newly identified, highly expressed transcript encoded by the duplicated exons. We propose these lost transcripts are non-functional side products necessary to transcribe the Yin and Yang transcripts in the same cells. Our work demonstrates how gene sharing, through the production of multiple isoforms, can precede the creation of new, independent genes.

Xu, W. et al. (2015) International Worm Meeting "A laboratory adaptation in the nucleosome remodeling factor nurf-1 in C.elegans regulating epigenetic changes in the nervous system."

McGrath, P.T., Xu, W.

[

International Worm Meeting,

2015]

Chromatin remodeling plays a central role in epigenetics, which controls many aspects of cellular development and is associated with human cognitive dysfunction such as Alzheimer's disease. The mechanism of how these complex traits work remains elusive, so research on model organism Caenorhabditis elegans may enhance our understanding of the genetic basis of chromatin-remodeling related neuronal signaling pathways. Quantitative trait locus (QTL) mapping on a number of traits between N2 and another laboratory adapted strain LSJ2 identified a causative genetic variant within the nucleosome remodeling factor (nurf-1) gene variant. nurf-1 seems to be involved in a number of traits controlled by the nervous system, including egg-laying rate and dauer formation. nurf-1, which has multiple isoforms resulting from alternative splicing, is able to cooperate with ISWI ATPase and transcription factors to regulate histone occupancy on sequence-specific DNA regions. To explore its molecular and cellular functions, we are using co-conversion CRISPR to engineer stop codons within various exons, create loxP sites to inhibit gene function in specific neurons, or create epitope and fluorescent fusions. After assaying these edited strains, we will be able to uncover the functional process and cellular site of action of NURF-1. Further in vivo and in vitro pull down assays will identify specific genes that nurf-1 regulates. This effort can expand our knowledge of neuronal regulation through chromatin remodeling, and it may also provide therapeutic opportunities for neuronal diseases.

Xu, W. et al. (2017) International Worm Meeting "CRISPR/Cas9-based dissection of a genetically complex, pleiotropic chromatin-remodeling gene under selection in laboratory growth conditions."

McGrath, P., Xu, W.

[

International Worm Meeting,

2017]

There is general interest in understanding the genetic basis of adaptation to new environmental conditions. In the process of studying adaptation of LSJ2, a sister strain of N2 that grew in liquid axenic media for over 50 years, we identified a 60bp deletion in nurf-1, which encodes a subunit of the NURF nucleosome remodeling factor complex. This mutation seems to change life history strategy of the worms towards K-mode type growth: animals live longer and grow slower but at the cost of later reproductive timing and reduced reproductive rate. Interestingly, the nurf-1 gene seems to be abnormally complex - it is predicted to encode 16 different isoforms, suggesting that nurf-1 was targeted by evolution due to its genetic complexity. These predicted isoforms include a full-length version containing a DDT domain necessary for interaction with ISWI ATPase, domains necessary for interactions with transcription factors, and two PHD finger domains and a bromodomain that recognize histone marks H3K4me3 and H4K16Ac. However, other predicted isoforms contain subsets of these domains. In order to study and validate the nurf-1 isoforms, we first validated 6 independent transcriptional start sites using promoter::GFP fusions. We then introduced stop codons in 8 exons using CRISPR/Cas9 genome editing to knock out isoforms of interest. For isoforms with unique exons, we used these mutations to evaluate their role in growth and reproduction. For isoforms without unique exons, we used compound heterozygotes to create strains lacking specific isoforms. Surprisingly, the long form of nurf-1 (the a isoform) that contains all functional domains and is the primary isoform in vertebrates seems to have no effect on our measured biological traits. But three short isoforms - b,d and o forms - had independent effects on growth and egg laying. This is unexpected because d and o isoforms lack the DDT domain necessary for interaction with ISWI, which is conventionally thought to be an essential nurf-1 partner. This suggests additional potential functions for nurf-1 besides the regulation of histone occupancy through interaction with ISWI. Using nurf-1.d cDNA extrachromosomal array rescue we demonstrated that we could independently rescue the growth phenotype, indicating these traits are independently regulated by different cells. In conclusion, we demonstrated nurf-1 functions in isoform and cell-specific manner and propose it might be involved in cellular processes other than through its conventional role in the NURF complex. Our work also demonstrates how CRISPR/Cas9 can be used to dissect a complex gene.

Xu W et al. (2024) Nat Commun "A lineage-resolved cartography of microRNA promoter activity in C. elegans empowers multidimensional developmental analysis."

Qi H, Wang Y, Hu S, Liu J, Xu W, Sun X, Fan D, Zhang H, Cong Y, Si R, Du Z, Zhao Z, Tao Z, Li Y, Bai Y, Xiao L

[

Nat Commun,

2024]

Elucidating the expression of microRNAs in developing single cells is critical for functional discovery. Here, we construct scCAMERA (single-cell cartography of microRNA expression based on reporter assay), utilizing promoter-driven fluorescent reporters in conjunction with imaging and lineage tracing. The cartography delineates the transcriptional activity of 54 conserved microRNAs in lineage-resolved single cells throughout C. elegans embryogenesis. The combinatorial expression of microRNAs partitions cells into fine clusters reflecting their function and anatomy. Notably, the expression of individual microRNAs exhibits high cell specificity and divergence among family members. Guided by cellular expression patterns, we identify developmental functions of specific microRNAs, including miR-1 in pharynx development and physiology, miR-232 in excretory canal morphogenesis by repressing NHR-25/NR5A, and a functional synergy between miR-232 and miR-234 in canal development, demonstrating the broad utility of scCAMERA. Furthermore, integrative analysis reveals that tissue-specific fate determinants activate microRNAs to repress protein production from leaky transcripts associated with alternative, especially neuronal, fates, thereby enhancing the fidelity of developmental fate differentiation. Collectively, our study offers rich opportunities for multidimensional expression-informed analysis of microRNA biology in metazoans.

Fire A et al. (1994) Worm Breeder's Gazette "Vectorology I: New lacZ Vectors (Building a Better Gene Trap)."

Fire A, Xu SQ

[

Worm Breeder's Gazette,

1994]

Vectorology I: New lacZ vectors ("building a better gene trap") Andrew Fire and SiQun Xu Carnegie Institution of Washington, Baltimore, Md 21210

K Omata et al. (1999) International C. elegans Meeting "Characterization of the neural circuit of C. elegans: model analysis of the touch response"

F Yonezawa, K Omata, K Kawamura

[

International C. elegans Meeting,

1999]

In order to characterize the neural circuit of C. elagans, we construct a simple model by making use of the data table completed recently by Oshio et al . [1]. We assume that the signal of a neuron is calculated by the product of the signals from the neighboring neurons, and we investigate the touch sensitivity to continuous stimuli described by sinusoidal functions as defined in the rage from 0.0 to 1.0. We calculate the responses of the motor neurons by changing the frequencies of the stimuli. In our calculations, we change only the frequency w PLM for the input signal to the sensory neuron PLM, while the frequency for the other sensory neurons ALM, AVM and PVM is fixed to be a same value w 0 . We show that the output signals from the motor neurons A and B oscillate in time. We measure the minima of the oscillation for each w PLM value. The plot of the minima versus w PLM shows different hehaviors for the case of the neuron A and B. As for the signals from the neuron A, the values of the minima are widely distributed between 0.0 and 1.0 for all w PLM . As for the signals from the neuron B, on the other hand, the features are different for different w PLM values. (a) In the high frequency region of w PLM / w 0 0.4, the oscillation is simple harmonic and there exists only one minimum value (I min = 0.0). (b) As w PLM / w 0 is decreased, another minimum appears at a certain frequency, and the bifurcation takes place discontinuously. This behavior is different from usual continuous bifurcation observed in nonlinear systems. After a few discontinuous branching occur, signals with five periods can be seen in the intermediate frequency region of 0.3 w PLM / w 0 w PLM / w 0 [1] K. Oshio et al. ; C. elegans synaptic connectivity data'', Technical Report, CCEP, Keio Future No.1 (1998).

Wang C et al. (2018) Nat Commun "Author Correction: Small-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan."

[

Nat Commun,

2018]

The originally published version of this Article contained an error in the spelling of the author Nathaniel W. Oswald, which was incorrectly given as Nathaniel W. Olswald. This has now been corrected inboth the PDF and HTML versions of the Article.

Nawa Y et al. (1985) Parasite Immunol "Defective protective capacity of W/Wv mice against Strongyloides ratti infection and its reconstitution with bone marrow cells."

Kotani M, Nawa Y, Kiyota M, Korenaga M

[

Parasite Immunol,

1985]

The susceptibility of congenitally anemic, and mast cell deficient W/Wv mice to infection with Strongyloides ratti was examined. After a primary infection, W/Wv mice showed greater and more persistent peak larval counts than did normal littermates. Worm expulsion was also slower in W/Wv mice than in +/+ mice. Furthermore, difference in susceptibility was expressed as early as 24 h after infection, suggesting not only that protective mechanisms of the gut but also of the connective tissue were defective in W/Wv mice. Reconstitution with bone marrow or spleen cells from +/+ mice was effective in restoring the protective response in W/Wv mice, whereas thymocytes or mesenteric lymph nodes had no effect. Both connective tissue and mucosal mast cells were repaired in W/Wv mice after marrow reconstitution and infection. Since relatively long incubation period was required for the expression of such reconstituting activities, bone marrow cells seem to contain precursor cells of the effector and/or regulator cells.

Casiraghi M et al. (2004) Int J Parasitol "Mapping the presence of Wolbachia pipientis on the phylogeny of filarial nematodes: evidence for symbiont loss during evolution."

Guerrero R, Bandi C, Franceschi A, Pocacqua V, Gardner SL, Casiraghi M, Martin C, Bain O

[

Int J Parasitol,

2004]

Wolbachia pipientis is a bacterial endosymbiont associated with arthropods and filarial nematodes. In filarial nematodes, W. pipientis has been shown to play an important role in the biology of the host and in the immuno-pathology of filariasis. Several species of filariae, including the most important parasites of humans and animals (e.g. Onchocerca volvulus, Wuchereria bancrofti and Dirofilaria immitis) have been shown to harbour these bacteria. Other filarial species, including an important rodent species (Acanthocheilonema viteae), which has been used as a model for the study of filariasis, do not appear to harbour these symbionts. There are still several open questions about the distribution of W. pipientis in filarial nematodes. Firstly the number of species examined is still limited. Secondly, it is not clear whether the absence of W. pipientis in negative species could represent an ancestral characteristic or the result of a secondary loss. Thirdly, several aspects of the phylogeny of filarial nematodes are still unclear and it is thus difficult to overlay the presence/absence of W. pipientis on a tree representing filarial evolution. Here we present the results of a PCR screening for W. pipientis in 16 species of filariae and related nematodes, representing different families/subfamilies. Evidence for the presence of W. pipientis is reported for five species examined for the first time (representing the genera Litomosoides, Litomosa and Dipetalonema); original results on the absence of this bacterium are reported for nine species; for the remaining two species, we have confirmed the absence of W. pipientis recently reported by other authors. In the positive species, the infecting W. pipientis bacteria have been identified through 16S rDNA gene sequence analysis. In addition to the screening for W. pipientis in 16 species, we have generated phylogenetic reconstructions based on mitochondrial gene sequences (12S rDNA; COI), including a total of 28 filarial species and related spirurid nematodes. The mapping of the presence/absence of W. pipientis on the trees generated indicates that these bacteria have possibly been lost during evolution along some lineages of filarial nematodes.

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