CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency
Open accessAbstract
CRISPRa corrects haploinsufficient obesity: Loss-of-function mutation in one gene copy, termed haploinsufficiency, can lead to insufficient protein levels and result in human disease. Matharu et al. tested whether a CRISPR-based activation system (CRISPRa) could rescue a haploinsufficient phenotype by increasing the gene expression levels of the existing normal copy (see the Perspective by Montefiori and Nobrega). By delivering this system into the mouse hypothalamus using adeno-associated virus, they rescued the obesity phenotype caused by haploinsufficiency of either of two genes known to promote obesity when mutated in mice and humans. These results highlight the translational potential of the CRISPR activation system to treat haploinsufficient disease. Science , this issue p. eaau0629 ; see also p. 231
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Structural studies including those using diffusion tensor imaging (DTI) and functional MRI (fMRI) have accelerated understanding of how altered neural circuits relate to clinical symptoms of ASD.
“structural studies including those using diffusion tensor imaging (DTI) 62 and functional MRI (fMRI) 63 have accelerated our understanding of how altered neural circuits relate to clinical symptoms of ASD 64,65”
From Autism spectrum disorder (2020) · cites this paper as [63]
The Discussion addresses neural mechanisms of obesity and CRISPR-mediated rescue in mice, not altered neural circuits and clinical symptoms of ASD. Searches for ASD, DTI, fMRI, and the claimed circuit–symptom relationship found no relevant passage in our copy. (LLM, conf=0.78)
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- Authors
- Matharu, N., Rattanasopha, S., Tamura, S., Maliskova, L., Wang, Y., Bernard, A., Hardin, A., Eckalbar, W. L., Vaisse, C., & Ahituv, N.
- Affiliations
- University of California, San Francisco (US)
- Chulalongkorn University (TH)
- Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA.
- Corresponding author
- Ahituv, Nadav
- ORCID
- Venue
- Science
- Published
- 2019-01-18
- Volume
- 363
- Issue
- 6424
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC6570489
- OpenAlex
- W2904738166
- Cited by
- 323
- References
- 58
- Citations by year
- 2026: 23 · 2025: 39 · 2024: 32 · 2023: 44 · 2022: 44 · 2021: 64 · 2020: 45 · 2019: 31
- FWCI
- 12.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (P30DK098722)
- National Institute of Mental Health (1R01MH109907)
- National Human Genome Research Institute (1R01CA197139, 1UM1HG009408)
- National Institute of General Medical Sciences (K12GM081266)
- National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK090382, R01DK106404, R01 DK60540-09)
- National Institute of Child Health and Human Development (1P01HD084387)
- UCSF Catalyst Program
- Mary Anne Koda-Kimble Seed Award for Innovation
- Royal Golden Jubilee Ph.D. Program (PHD/0071/2554)
- American Diabetes Association Mentor Based Award (7-12-MN-79)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- CRISPR activation, haploinsufficiency, obesity, hypothalamus, adeno-associated virus delivery, obesity-related genes, gene therapy
- MeSH terms
- Loss of Function Mutation, Dependovirus, Animals, Cell Line, Disease Models, Animal, Enhancer Elements, Genetic, Female, Gene Expression Regulation, Heterozygote, Hypothalamus, Male, Mice, Transgenic, Obesity, Phenotype, Promoter Regions, Genetic, Repressor Proteins, Weight Gain, Up-Regulation, Gene Transfer Techniques, Receptor, Melanocortin, Type 4, Mice, Basic Helix-Loop-Helix Proteins, Haploinsufficiency, Clustered Regularly Interspaced Short Palindromic Repeats
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