scholarly journals Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy

2016 ◽  
Vol 113 (22) ◽  
pp. E3091-E3100 ◽  
Author(s):  
Emma L. Ivansson ◽  
Kate Megquier ◽  
Sergey V. Kozyrev ◽  
Eva Murén ◽  
Izabella Baranowska Körberg ◽  
...  
Keyword(s):  
Gene Transcription ◽  
Nuclear Body ◽  
Body Protein ◽  
Modifier Locus ◽  
Naturally Occurring ◽  
Genome Wide ◽  
A Genome ◽  
Canine Chromosome ◽  
Degenerative Myelopathy ◽  
Lateral Sclerosis

Canine degenerative myelopathy (DM) is a naturally occurring neurodegenerative disease with similarities to some forms of amyotrophic lateral sclerosis (ALS). Most dogs that develop DM are homozygous for a common superoxide dismutase 1 gene (SOD1) mutation. However, not all dogs homozygous for this mutation develop disease. We performed a genome-wide association analysis in the Pembroke Welsh Corgi (PWC) breed comparing DM-affected and -unaffected dogs homozygous for the SOD1 mutation. The analysis revealed a modifier locus on canine chromosome 25. A haplotype within the SP110 nuclear body protein (SP110) was present in 40% of affected compared with 4% of unaffected dogs (P = 1.5 × 10−5), and was associated with increased probability of developing DM (P = 4.8 × 10−6) and earlier onset of disease (P = 1.7 × 10−5). SP110 is a nuclear body protein involved in the regulation of gene transcription. Our findings suggest that variations in SP110-mediated gene transcription may underlie, at least in part, the variability in risk for developing DM among PWCs that are homozygous for the disease-related SOD1 mutation. Further studies are warranted to clarify the effect of this modifier across dog breeds.

Copy-number variation in sporadic amyotrophic lateral sclerosis: a genome-wide screen

2008 ◽  
Vol 7 (4) ◽  
pp. 319-326 ◽  
Author(s):  
Hylke M Blauw ◽  
Jan H Veldink ◽  
Michael A van Es ◽  
Paul W van Vught ◽  
Christiaan GJ Saris ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Copy Number Variation ◽  
Copy Number ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Genome Wide ◽  
A Genome ◽  
Number Variation ◽  
Lateral Sclerosis

scholarly journals Genome-wide synthetic lethal CRISPR screen identifies FIS1 as a genetic interactor of ALS-linked C9ORF72

2019 ◽  
Author(s):  
Noori Chai ◽  
Michael S. Haney ◽  
Julien Couthouis ◽  
David W. Morgens ◽  
Alyssa Benjamin ◽  
...  
Keyword(s):  
Genetic Interaction ◽  
Mitochondrial Fission ◽  
Loss Of Function ◽  
Synthetic Lethal ◽  
Genome Wide ◽  
A Genome ◽  
Crispr Screen ◽  
Insight Into ◽  
Mitochondrial Membrane Protein ◽  
Lateral Sclerosis

AbstractMutations in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis (ALS). Both toxic gain of function and loss of function pathogenic mechanisms have been proposed. Accruing evidence from mouse knockout studies point to a role for C9ORF72 as a regulator of immune function. To provide further insight into its cellular function, we performed a genome-wide synthetic lethal CRISPR screen in human myeloid cells lacking C9ORF72. We discovered a strong synthetic lethal genetic interaction between C9ORF72 and FIS1, which encodes a mitochondrial membrane protein involved in mitochondrial fission and mitophagy. Mass spectrometry experiments revealed that in C9ORF72 knockout cells, FIS1 strongly bound to a class of immune regulators that activate the receptor for advanced glycation end (RAGE) products and trigger inflammatory cascades. These findings present a novel genetic interactor for C9ORF72 and suggest a compensatory role for FIS1 in suppressing inflammatory signaling in the absence of C9ORF72.

scholarly journals DNA methylation of intragenic CpG islands depends on their transcriptional activity during differentiation and disease

2017 ◽  
Vol 114 (36) ◽  
pp. E7526-E7535 ◽  
Author(s):  
Danuta M. Jeziorska ◽  
Robert J. S. Murray ◽  
Marco De Gobbi ◽  
Ricarda Gaentzsch ◽  
David Garrick ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Cpg Islands ◽  
Naturally Occurring ◽  
Genome Wide ◽  
A Genome ◽  
Primary Determinant ◽  
Development And Differentiation ◽  
Intrinsic Capacity

The human genome contains ∼30,000 CpG islands (CGIs). While CGIs associated with promoters nearly always remain unmethylated, many of the ∼9,000 CGIs lying within gene bodies become methylated during development and differentiation. Both promoter and intragenic CGIs may also become abnormally methylated as a result of genome rearrangements and in malignancy. The epigenetic mechanisms by which some CGIs become methylated but others, in the same cell, remain unmethylated in these situations are poorly understood. Analyzing specific loci and using a genome-wide analysis, we show that transcription running across CGIs, associated with specific chromatin modifications, is required for DNA methyltransferase 3B (DNMT3B)-mediated DNA methylation of many naturally occurring intragenic CGIs. Importantly, we also show that a subgroup of intragenic CGIs is not sensitive to this process of transcription-mediated methylation and that this correlates with their individual intrinsic capacity to initiate transcription in vivo. We propose a general model of how transcription could act as a primary determinant of the patterns of CGI methylation in normal development and differentiation, and in human disease.

scholarly journals A genome-wide linkage scan in German shepherd dogs localizes canine platelet procoagulant deficiency (Scott syndrome) to canine chromosome 27

Gene ◽  
2010 ◽  
Vol 450 (1-2) ◽  
pp. 70-75 ◽  
Author(s):  
Marjory Brooks ◽  
Krystal Etter ◽  
James Catalfamo ◽  
Abra Brisbin ◽  
Carlos Bustamante ◽  
...  
Keyword(s):  
German Shepherd ◽  
Genome Wide ◽  
A Genome ◽  
Canine Chromosome

scholarly journals Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study

2010 ◽  
Vol 9 (10) ◽  
pp. 978-985 ◽  
Author(s):  
Hannu Laaksovirta ◽  
Terhi Peuralinna ◽  
Jennifer C Schymick ◽  
Sonja W Scholz ◽  
Shaoi-Lin Lai ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Chromosome 9P21 ◽  
Genome Wide ◽  
A Genome ◽  
Lateral Sclerosis

scholarly journals C9orf72andUNC13Aare shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: A genome-wide meta-analysis

2014 ◽  
Vol 76 (1) ◽  
pp. 120-133 ◽  
Author(s):  
Frank P. Diekstra ◽  
Vivianna M. Van Deerlin ◽  
John C. van Swieten ◽  
Ammar Al-Chalabi ◽  
Albert C. Ludolph ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Meta Analysis ◽  
Genome Wide ◽  
A Genome ◽  
Shared Risk ◽  
Lateral Sclerosis

scholarly journals Regulation of Pol II Pausing Is Involved in Daily Gene Transcription in the Mouse Liver

2018 ◽  
Vol 33 (4) ◽  
pp. 350-362 ◽  
Author(s):  
Jialou Zhu ◽  
Chengwei Li ◽  
Changxia Gong ◽  
Xiaodong Li
Keyword(s):  
Gene Transcription ◽  
Mouse Liver ◽  
Phase Distribution ◽  
Gene Body ◽  
Pol Ii ◽  
Genome Wide ◽  
A Genome ◽  
Pol Ii Pausing ◽  
Transcriptional Output

The circadian clock orchestrates gene expression rhythms. Regulation at the level of gene transcription is essential for molecular and cellular rhythms. Pol II pause release is a critical step of transcription regulation. However, whether and how Pol II pause release is regulated during daily transcription have not been characterized. In this study, we performed Pol II ChIP-seq across the day in the mouse liver and quantitatively analyzed binding signals within the transcription start site (TSS) region and the gene body. We frequently found discordant changes between Pol II near the TSS ([Pol II]TSS, paused Pol II) and that within the gene body ([Pol II]GB, transcribing Pol II) across the genome, with only [Pol II]GB always reflecting transcription of clock and clock-controlled genes. Accordingly, Pol II traveling ratios of more than 7000 genes showed significant daily changes (>1.5-fold). Therefore, there is widespread regulation of Pol II pausing in the mouse liver. Interestingly, gene transcription rhythms exhibited a bimodal phase distribution. The transcription of ~400 genes peaked near ZT0, coincident with a genome-wide increase in [Pol II]TSS and traveling ratio (TR). The transcription of ~300 other genes peaked ~12 h later, when there was a global decrease in [Pol II]TSS and TR. ChIP-seq against TATA-binding protein (Tbp), a preinitiation complex (PIC) component, revealed that Pol II recruitment mainly played an indirect role in transcriptional output, with transcriptional termination and pause release functioning prominently in determining the fate of initiated Pol II and its pausing status. Taken together, our results revealed a critical, albeit complex role of Pol II pausing control in regulating the temporal output of gene transcription.

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