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Promoter or enhancer activation by CRISPRa rescues haploinsufficiency caused obesity

ABSTRACT: Promoter or enhancer activation by CRISPRa rescues haploinsufficiency caused obesity

PROVIDER: PRJNA445383 | ENA |

REPOSITORIES: ENA

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Promoter or enhancer activation by CRISPRa rescues haploinsufficiency caused obesity

Project description:Haploinsufficiency, having only one functional copy of a gene, leads to a wide-range of human diseases. Using obesity as a disease model, we tested whether haploinsufficiency can be rescued by CRISPR-mediated activation (CRISPRa) of the normal allele. Haploinsufficiency of either SIM1 or MC4R, results in severe obesity in humans and mice. In transgenic mice, CRISPRa targeting of the Sim1 promoter or its ~270kb distant hypothalamic enhancer, rescued the obesity phenotype in Sim1 heterozygous mice. Interestingly, despite using a ubiquitous promoter for CRISPRa, Sim1 was upregulated only in tissues where the promoter or enhancer are active, suggesting that cis-regulatory elements can determine CRISPRa tissue-specificity. To evaluate the potential therapeutic use of CRISPRa, we injected CRISPRa-rAAV into the hypothalamus, leading to reversal of the obesity phenotype in Sim1 and Mc4r heterozygous mice. Our results show that CRISPRa can be developed as a gene regulation therapy (GRT) to treat altered gene dosage diseases.

2018-12-17 | GSE112250 | GEO

CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency.

Project description: Not available

| S-EPMC6570489 | biostudies-literature

CRISPR activation rescues electrophysiological abnormalities in SCN2A haploinsufficiency associated autism spectrum disorder

Project description:CRISPR activation rescues electrophysiological abnormalities in SCN2A haploinsufficiency associated autism spectrum disorder

| PRJNA796834 | ENA

CRISPR activation rescues electrophysiological abnormalities in SCN2A haploinsufficiency associated autism spectrum disorder

Project description:Here we are testing the effects and measuring mRNA expression of CRISPRa targeting the promoter of mouse Scn2a in Neuro2a cells

2022-04-01 | GSE193605 | GEO

tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase

Project description:tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase

| PRJNA673697 | ENA

Telomere Length Protects Mice from Human Disease Phenotype Caused By Notch1 Haploinsufficiency

Project description:Diseases caused by gene haploinsufficiency in humans commonly lack a phenotype in mice heterozygous for the orthologous factor, although the source of this discrepancy is unknown. The inability to accurately model human disease in mice impedes the study of complex phenotypes and critically limits the discovery and testing of potential therapeutics. Laboratory mice have longer telomeres (>40 kilobases (kb)) compared to humans (~5-15 kb), potentially protecting them from age-related disease caused by haploinsufficiency. In humans, heterozygous non-sense mutations in the transcription factor, NOTCH1 (N1), lead to severe age-dependent aortic valve (AV) calcification. However, mice heterozygous for N1 do not develop calcific AV disease (CAVD)5. Here, we show that telomere shortening is sufficient to elicit age-dependent cardiac valve disease in N1+/- mice that closely mimics the human disease and that progressive shortening correlates with severity of disease, extending to AV thickening in the neonate. N1 haploinsufficiency led to increased proliferation in valves that further reduced telomere length. Calcified AVs exhibited downregulation of osteoclast factors and upregulation of pro-calcific regulatory nodes concordant with gene network alterations in human N1 heterozygous endothelial cells. Dysregulated genes in valves were enriched for those that have promoters normally contacted by telomere looping. These findings reveal a critical role for telomere length in a mouse model of age-dependent human disease that may have broader implications and provides an in vivo model in which to test therapeutic candidates to prevent or delay the progression of CAVD.

2017-08-22 | GSE83963 | GEO

STRT RNAseq of pluripotent stem cells reprogrammed with CRISPRa

Project description:Transcriptome comparison of CRISPRa induced human pluripotent stem cell lines, control iPSC line induced with Sendai viral vectors, H9 embryonic stem cell line and human foreskin fibroblasts.

2018-06-07 | E-MTAB-6185 | biostudies-arrayexpress

tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase

Project description:Heterozygous mutations in six tRNA synthetase genes cause Charcot-Marie-Tooth (CMT) peripheral neuropathy. CMT-mutant glycyl- or tyrosyl-tRNA synthetases inhibit global protein synthesis by an unknown mechanism, independent of aminoacylation activity. We report that tRNAGly overexpression rescues protein synthesis and peripheral neuropathy phenotypes in Drosophila and mouse models of CMT caused by glycyl-tRNA synthetase (GlyRS) mutations (CMT2D). Kinetic experiments revealed that CMT-mutant GlyRS bind tRNAGly, but display markedly slow release rates. This tRNAGly sequestration may deplete the cellular tRNAGly pool, leading to insufficient glycyl-tRNAGly supply to the ribosome and translation deficit.

2021-09-07 | GSE160584 | GEO

TAB2 haploinsufficiency

Project description:TAB2 haploinsufficiency

| PRJNA747894 | ENA

DNA methylome analysis of human pluripotent stem cells reprogrammed with CRISPRa

Project description:Comparison of DNA methylation in CRISPRa induced human pluripotent stem cell lines, control iPSC line induced with Sendai viral vectors, H9 embryonic stem cell line and human foreskin fibroblasts.

2018-06-07 | E-MTAB-6194 | biostudies-arrayexpress

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