scholarly journals Mutant Huntingtin Affects Diabetes and Alzheimer’s Markers in Human and Cell Models of Huntington’s Disease

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 962 ◽  
Author(s):  
Gepoliano Chaves ◽  
John Stanley ◽  
Nader Pourmand
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Genome Wide Association Study ◽  
Cell Model ◽  
Statistical Significance ◽  
Mutant Huntingtin ◽  
Rna Seq ◽  
Genome Wide ◽  
A Genome ◽  
Reliable Model

A higher incidence of diabetes was observed among family members of individuals affected by Huntington’s Disease with no follow-up studies investigating the genetic nature of the observation. Using a genome-wide association study (GWAS), RNA sequencing (RNA-Seq) analysis and western blotting of Rattus norvegicus and human, we were able to identify that the gene family of sortilin receptors was affected in Huntington’s Disease patients. We observed that less than 5% of SNPs were of statistical significance and that sortilins and HLA/MHC gene expression or SNPs were associated with mutant huntingtin (mHTT). These results suggest that ST14A cells derived from R. norvegicus are a reliable model of HD, since sortilins were identified through analysis of the transcriptome in these cells. These findings help highlight the genes involved in mechanisms targeted by diabetes drugs, such as glucose transporters as well as proteins controlling insulin release related to mHTT. To the best of our knowledge, this is the first GWAS using RNA-Seq data from both ST14A rat HD cell model and human Huntington’s Disease.

scholarly journals Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

2017 ◽  
Vol 16 (9) ◽  
pp. 701-711 ◽  
Author(s):  
Davina J Hensman Moss ◽  
Antonio F Pardiñas ◽  
Douglas Langbehn ◽  
Kitty Lo ◽  
Blair R Leavitt ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Association Study ◽  
Huntington’S Disease ◽  
Disease Progression ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

scholarly journals Osmolytes dynamically regulate mutant Huntingtin aggregation and CREB function in Huntington’s disease cell models

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Shreyaas Aravindan ◽  
Samantha Chen ◽  
Hannaan Choudhry ◽  
Celine Molfetta ◽  
Kuang Yu Chen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Inclusion Bodies ◽  
Cell Model ◽  
Mutant Huntingtin ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered ◽  
Disease Protein ◽  
Disease Cell

Abstract Osmolytes are organic solutes that change the protein folding landscape shifting the equilibrium towards the folded state. Herein, we use osmolytes to probe the structuring and aggregation of the intrinsically disordered mutant Huntingtin (mHtt) vis-a-vis the pathogenicity of mHtt on transcription factor function and cell survival. Using an inducible PC12 cell model of Huntington’s disease (HD), we show that stabilizing polyol osmolytes drive the aggregation of Htt103QExon1-EGFP from a diffuse ensemble into inclusion bodies (IBs), whereas the destabilizing osmolyte urea does not. This effect of stabilizing osmolytes is innate, generic, countered by urea, and unaffected by HSP70 and HSC70 knockdown. A qualitatively similar result of osmolyte-induced mHtt IB formation is observed in a conditionally immortalized striatal neuron model of HD, and IB formation correlates with improved survival under stress. Increased expression of diffuse mHtt sequesters the CREB transcription factor to repress CREB-reporter gene activity. This repression is mitigated either by stabilizing osmolytes, which deplete diffuse mHtt or by urea, which negates protein–protein interaction. Our results show that stabilizing polyol osmolytes promote mHtt aggregation, alleviate CREB dysfunction, and promote survival under stress to support the hypothesis that lower molecular weight entities of disease protein are relevant pathogenic species in neurodegeneration.

scholarly journals Transcriptomic and Genome-wide Association Study Reveal Long Noncoding RNAs Responding to Nitrogen Deficiency in Maize

2020 ◽  
Author(s):  
PENG MA ◽  
Xiao Zhang ◽  
Bowen Luo ◽  
Zhen Chen ◽  
Xuan He ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Nitrogen Deficiency ◽  
Snp Array ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Genome Wide Association ◽  
Rna Seq ◽  
Genome Wide ◽  
A Genome

Abstract Background: Long noncoding RNAs (lncRNAs) play important roles in essential biological processes. However, our understanding of lncRNAs as competing endogenous RNAs (ceRNAs) and their responses to nitrogen stress is still limited.Results: Here, we surveyed the lncRNAs and miRNAs in maize inbred line P178 leaves and roots at the seedling stage under high-nitrogen and low-nitrogen conditions using lncRNA-Seq and small RNA-Seq. A total of 894 differentially expressed lncRNAs and 38 different miRNAs were identified. Co-expression analysis found two lncRNAs and four lncRNA-targets could competitively combine with ZmmiR159 and ZmmiR164, respectively. To dissect the genetic regulatory by which lncRNAs might enable adaptation to limited nitrogen availability. An association mapping panel containing a high-density single–nucleotide polymorphism (SNP) array (56,110 SNPs) combined with variable LN resistance-related phenotypes obtained from hydroponics was used for a genome-wide association study (GWAS). By combining GWAS and RNA-Seq, 170 differently expressed lncRNAs within the range of significant markers were screened. Moreover, 40 consistently LN-responsive genes including those involved in glutamine biosynthesis and nitrogen acquisition in root were identified. Transient expression assays in Nicotiana benthamiana demonstrated LNC_002923 could inhabit ZmmiR159-guided cleavage of Zm00001d015521. Conclusions: These lncRNAs containing trait-associated significant SNPs could consider to be related to root development and nutrient utilization. Taken together, the results of our study can provide new insights into the potential regulatory roles of lncRNAs in response to LN stress, and give valuable information for further screening of candidates as well as the improvement of maize regarding LN-responsive resistance.

scholarly journals Transcriptomic and genome-wide association study reveal long noncoding RNAs responding to nitrogen deficiency in maize

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Peng Ma ◽  
Xiao Zhang ◽  
Bowen Luo ◽  
Zhen Chen ◽  
Xuan He ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Nitrogen Deficiency ◽  
Snp Array ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Genome Wide Association ◽  
Rna Seq ◽  
Genome Wide ◽  
A Genome

Abstract Background Long noncoding RNAs (lncRNAs) play important roles in essential biological processes. However, our understanding of lncRNAs as competing endogenous RNAs (ceRNAs) and their responses to nitrogen stress is still limited. Results Here, we surveyed the lncRNAs and miRNAs in maize inbred line P178 leaves and roots at the seedling stage under high-nitrogen (HN) and low-nitrogen (LN) conditions using lncRNA-Seq and small RNA-Seq. A total of 894 differentially expressed lncRNAs and 38 different miRNAs were identified. Co-expression analysis found that two lncRNAs and four lncRNA-targets could competitively combine with ZmmiR159 and ZmmiR164, respectively. To dissect the genetic regulatory by which lncRNAs might enable adaptation to limited nitrogen availability, an association mapping panel containing a high-density single–nucleotide polymorphism (SNP) array (56,110 SNPs) combined with variable LN tolerant-related phenotypes obtained from hydroponics was used for a genome-wide association study (GWAS). By combining GWAS and RNA-Seq, 170 differently expressed lncRNAs within the range of significant markers were screened. Moreover, 40 consistently LN-responsive genes including those involved in glutamine biosynthesis and nitrogen acquisition in root were identified. Transient expression assays in Nicotiana benthamiana demonstrated that LNC_002923 could inhabit ZmmiR159-guided cleavage of Zm00001d015521. Conclusions These lncRNAs containing trait-associated significant SNPs could consider to be related to root development and nutrient utilization. Taken together, the results of our study can provide new insights into the potential regulatory roles of lncRNAs in response to LN stress, and give valuable information for further screening of candidates as well as the improvement of maize resistance to LN stress.

A genome-wide association study of colorectal cancer in Mexican mestizos suggest novel common tumor-risk variants

2020 ◽  
Author(s):  
AUGUSTO Rojas-Martinez ◽  
Valentina Colistro ◽  
Raquel Cruz ◽  
Clara Ruiz ◽  
Inés Quintela ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Latin American ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Statistical Significance ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Autosomal Snps ◽  
Genome Wide ◽  
A Genome

Abstract Background: Genome-wide association studies (GWAS) for colorectal cancer (CRC) have detected high-risk genetic variants associated with CRC in several ethnic groups, but Latin American communities are still underrepresented. The aim was to identify variants related to CRC in an admixed Latin American population. Methods: The study was performed in 831 cases and 881 controls from Mexico, who were genotyped for 1,006,703 autosomal SNPs. Logistic regression was carried out including covariants, such as sex, age and genetic ancestry. Lastly, we performed a sequence-kernel association test (SKAT) to consider the joint effect of several SNPs lying in genes.Results: Eight chromosomal regions reached genome-wide significance level ( p < 5×10 -8 ): 1p36.22, 1p31.1, 1q42.13, 6p22, 7p14.1, 12q24.32, 16q12.2 and 21q22.2 and 63 variants reached borderline statistical significance ( p < 1×10 − 6 ). SKAT analysis detected 13 loci associated with CRC, none of them previously associated with CRC. Conclusions: We found 8 SNPs and 13 loci associated with CRC. These signals may contribute to enrich the panoply of genes involved with CRC. Further analyses remain to be done to validate the associations in other Latin American populations. This study highlights the importance of conducting GWAS in poorly explored admixed populations.

scholarly journals Clusters of polymorphic transmembrane genes control resistance to schistosomes in snail vectors

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Jacob A Tennessen ◽  
Stephanie R Bollmann ◽  
Ekaterina Peremyslova ◽  
Brent A Kronmiller ◽  
Clint Sergi ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Genomic Region ◽  
Amino Acid Residues ◽  
Rna Seq ◽  
Intermediate Hosts ◽  
Genome Wide ◽  
A Genome ◽  
Snail Proteins ◽  
Genome Assemblies ◽  
Host Parasite

Schistosomiasis is a debilitating parasitic disease infecting hundreds of millions of people. Schistosomes use aquatic snails as intermediate hosts. A promising avenue for disease control involves leveraging innate host mechanisms to reduce snail vectorial capacity. In a genome-wide association study of Biomphalaria glabrata snails, we identify genomic region PTC2 which exhibits the largest known correlation with susceptibility to parasite infection (>15 fold effect). Using new genome assemblies with substantially higher contiguity than the Biomphalaria reference genome, we show that PTC2 haplotypes are exceptionally divergent in structure and sequence. This variation includes multi-kilobase indels containing entire genes, and orthologs for which most amino acid residues are polymorphic. RNA-Seq annotation reveals that most of these genes encode single-pass transmembrane proteins, as seen in another resistance region in the same species. Such groups of hyperdiverse snail proteins may mediate host-parasite interaction at the cell surface, offering promising targets for blocking the transmission of schistosomiasis.

scholarly journals N-Terminal Proteolysis of Full-Length Mutant Huntingtin in an Inducible PC12 Cell Model of Huntington’s Disease

Cell Cycle ◽  
2007 ◽  
Vol 6 (23) ◽  
pp. 2970-2981 ◽  
Author(s):  
Tamara Ratovitski ◽  
Masayuki Nakamura ◽  
James D'Ambola ◽  
Ekaterine Chighladze ◽  
Yideng Liang ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Pc12 Cell ◽  
Cell Model ◽  
Full Length ◽  
Mutant Huntingtin

scholarly journals Genetic Variation in PADI6-PADI4 on 1p36.13 Is Associated with Common Forms of Human Generalized Epilepsy

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1441
Author(s):  
Russell J. Buono ◽  
Jonathan P. Bradfield ◽  
Zhi Wei ◽  
Michael R. Sperling ◽  
Dennis J. Dlugos ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Genome Wide Association Study ◽  
Focal Epilepsy ◽  
Statistical Significance ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Control Of Gene Expression ◽  
Genome Wide ◽  
A Genome ◽  
Generalized Epilepsy

We performed a genome-wide association study (GWAS) to identify genetic variation associated with common forms of idiopathic generalized epilepsy (GE) and focal epilepsy (FE). Using a cohort of 2220 patients and 14,448 controls, we searched for single nucleotide polymorphisms (SNPs) associated with GE, FE and both forms combined. We did not find any SNPs that reached genome-wide statistical significance (p ≤ 5 × 10−8) when comparing all cases to all controls, and few SNPs of interest comparing FE cases to controls. However, we document multiple linked SNPs in the PADI6-PADI4 genes that reach genome-wide significance and are associated with disease when comparing GE cases alone to controls. PADI genes encode enzymes that deiminate arginine to citrulline in molecular pathways related to epigenetic regulation of histones and autoantibody formation. Although epilepsy genetics and treatment are focused strongly on ion channel and neurotransmitter mechanisms, these results suggest that epigenetic control of gene expression and the formation of autoantibodies may also play roles in epileptogenesis.

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