Engineering Biological C–H Functionalization Leads to Allele-Specific Regulation of Histone Demethylases

2016 ◽  
Vol 138 (41) ◽  
pp. 13505-13508 ◽  
Author(s):  
Megan Breski ◽  
Debasis Dey ◽  
Sara Obringer ◽  
Babu Sudhamalla ◽  
Kabirul Islam
Keyword(s):  
Histone Demethylases ◽  
Allele Specific ◽  
Specific Regulation

scholarly journals Transcription of the IL10 gene reveals allele-specific regulation at the mRNA level

2004 ◽  
Vol 13 (16) ◽  
pp. 1755-1762 ◽  
Author(s):  
Fina A.S. Kurreeman ◽  
Joris J.M. Schonkeren ◽  
Bastiaan T. Heijmans ◽  
Rene E.M. Toes ◽  
Tom W.J. Huizinga
Keyword(s):  
Mrna Level ◽  
Il10 Gene ◽  
Allele Specific ◽  
Specific Regulation

Abstract P117: Blood Pressure Heterosis And Genotype-Specific Regulation Of C17h6orf52

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Karen C Clark ◽  
Valerie Wagner ◽  
Anne E Kwitek
Keyword(s):  
Blood Pressure ◽  
Hybrid Vigor ◽  
Female Rats ◽  
Lower Systolic Blood Pressure ◽  
Male And Female Rats ◽  
Protein Functions ◽  
Show Evidence ◽  
Normal Chow ◽  
Allele Specific ◽  
Specific Regulation

Although blood pressure (BP) is highly heritable, the genetic etiology is complex, and causative genes do not completely explain observed variation. Using the Lyon Hypertensive (LH) rat—a well-characterized polygenic inbred model—we previously identified a novel candidate gene ( C17h6orf52 ) as a master regulator of gene expression regulating cardiometabolic traits. CRISPR-Cas9 gene editing was used to generate a mutation in C17h6orf52 , and blood pressure in homozygous wildtype (WT), heterozygous (HET) and homozygous mutant (MUT) females was characterized via radiotelemetry. Herein, we show evidence of BP heterosis (i.e. hybrid vigor) in females from the C17h6orf52 strain. Systolic (SBP) and diastolic (DBP) pressures (mmHg) were determined in WT, HET, and MUT male and female rats on normal chow (CHOW), and 4% salt (NaCl) diet (to determine salt sensitivity). All measures are presented as mean±SEM, and significant results are indicated according to statistical test. No significant differences were identified in males, but the HET females (n=5) had significantly lower systolic blood pressure than either WT (n=7) or MUT (n=8) at both baseline and salt-stressed conditions: SBP-CHOW: (WT: 144±3.28; HET: 136.0±0.83 * ; MUT: 142.6±2.13)DBP-CHOW: (WT: 98.3±2.29; HET: 94.0±0.68; MUT: 97.4±1.76)SBP-NaCl: (WT: 150.4±3.40; HET: 142.2±1.19 * ; MUT: 150.2±1.83)DBP-NaCl: (WT: 103.3±2.75; HET: 98.2±1.68; MUT: 103.1±1.68) Tissues were collected to assess C17h6orf52 expression relative to WT, displayed below as confidence intervals. While there were no differences between WT and MUT expression, liver C17h6orf52 was significantly overexpressed in heterozygous females. C17h6orf52 2^-ddCT: (WT: 0.91-1.09, n=8; HET: 1.33-1.73 $ , n=5; MUT: 0.85-1.19, n=8) There were no striking differences in any metabolic phenotypes, such as body weight and adiposity, thus these data suggest that C17h6orf52 is protective against increases in blood pressure specifically. Continued study will attempt to tease apart allele-specific regulation and protein functions in heterozygous animals of both sexes. * p<0.05 by Kruskal-Wallis $ p<0.05 by 1-WAY ANOVA

Allele-Specific regulation of the human angiotensinogen gene by dexamethasone: implications for human hypertension

2015 ◽  
Vol 9 (4) ◽  
pp. e11
Author(s):  
Sudhir Jain ◽  
Anita Rana ◽  
Nitin Puri ◽  
Ashok Kumar
Keyword(s):  
Human Hypertension ◽  
Angiotensinogen Gene ◽  
Allele Specific ◽  
Specific Regulation

scholarly journals Allele-specific regulation of DISC1 expression by miR-135b-5p

2013 ◽  
Vol 22 (6) ◽  
pp. 840-843 ◽  
Author(s):  
Mari Rossi ◽  
Helena Kilpinen ◽  
Mikko Muona ◽  
Ida Surakka ◽  
Catherine Ingle ◽  
...  
Keyword(s):  
Allele Specific ◽  
Specific Regulation

scholarly journals A G316A Polymorphism in the Ornithine Decarboxylase Gene Promoter Modulates MYCN-Driven Childhood Neuroblastoma

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1807
Author(s):  
Laura D. Gamble ◽  
Stefania Purgato ◽  
Michelle J. Henderson ◽  
Simone Di Giacomo ◽  
Amanda J. Russell ◽  
...  
Keyword(s):  
Ornithine Decarboxylase ◽  
Gene Promoter ◽  
Mycn Amplification ◽  
Study Cohort ◽  
Polyamine Biosynthesis ◽  
Single Nucleotide ◽  
Allele Specific ◽  
Increased Sensitivity ◽  
Specific Regulation ◽  
Transcriptional Target

Ornithine decarboxylase (ODC1), a critical regulatory enzyme in polyamine biosynthesis, is a direct transcriptional target of MYCN, amplification of which is a powerful marker of aggressive neuroblastoma. A single nucleotide polymorphism (SNP), G316A, within the first intron of ODC1, results in genotypes wildtype GG, and variants AG/AA. CRISPR-cas9 technology was used to investigate the effects of AG clones from wildtype MYCN-amplified SK-N-BE(2)-C cells and the effect of the SNP on MYCN binding, and promoter activity was investigated using EMSA and luciferase assays. AG clones exhibited decreased ODC1 expression, growth rates, and histone acetylation and increased sensitivity to ODC1 inhibition. MYCN was a stronger transcriptional regulator of the ODC1 promoter containing the G allele, and preferentially bound the G allele over the A. Two neuroblastoma cohorts were used to investigate the clinical impact of the SNP. In the study cohort, the minor AA genotype was associated with improved survival, while poor prognosis was associated with the GG genotype and AG/GG genotypes in MYCN-amplified and non-amplified patients, respectively. These effects were lost in the GWAS cohort. We have demonstrated that the ODC1 G316A polymorphism has functional significance in neuroblastoma and is subject to allele-specific regulation by the MYCN oncoprotein.

scholarly journals Pervasive allele-specific regulation on RNA decay in hybrid mice

2018 ◽  
Vol 1 (2) ◽  
pp. e201800052 ◽  
Author(s):  
Wei Sun ◽  
Qingsong Gao ◽  
Bernhard Schaefke ◽  
Yuhui Hu ◽  
Wei Chen
Keyword(s):  
Genetic Variants ◽  
Phenotypic Diversity ◽  
Decay Rates ◽  
Rna Decay ◽  
Rna Transcription ◽  
F1 Hybrid ◽  
Significant Difference ◽  
Allelic Differences ◽  
Allele Specific ◽  
Specific Regulation

Cellular RNA abundance is determined by both RNA transcription and decay. Therefore, change in RNA abundance, which can drive phenotypic diversity between different species, could arise from genetic variants affecting either process. However, previous studies in the evolution of RNA expression have been largely focused on transcription. Here, to globally investigate the effects of cis-regulatory divergence on RNA decay in mammals for the first time, we quantified allele-specific differences in RNA decay rates (ASD) in an F1 hybrid mouse. Out of 8,815 genes with sufficient data, we identified 621 genes exhibiting significant cis-divergence. Systematic analysis of these genes revealed that the genetic variants affecting microRNA binding and RNA secondary structures contribute to the observed divergences. Finally, we demonstrated that although the divergences in RNA abundance were predominantly determined by allelic differences in RNA transcription, most genes with significant ASD did not exhibit significant difference in RNA abundance. For these genes, the apparently compensatory effect between the allelic differences in RNA transcription and ASD suggests that changes in RNA decay could serve as important means to stabilize RNA abundances during mammalian evolution.

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