- Predisposition to extreme obesity is controlled by genes
- Mutations in single copies of the genes - SIM1 and MCR4 are mostly responsible for severe obesity in patients
- A new system CRISPRa (activation) to amplify the activity of the two obesity genes without actually making an edit
- CRISPRa regulation produced more SIM1 and MCR4 and avoided extreme obesity and this was a long-lasting change
CRIPSR could be used to
prevent obesity with predispositions to weight gain, reveals a new study published in the journal Science, researchers
at the University of San Francisco (UCSF).
Predisposition to extreme obesity is controlled by genes. Mutations in single copies of the genes - SIM1 and MCR4 are mostly responsible for severe obesity in patients.
Two healthy copies of the gene are necessary to regulate hunger and satiation. If one copy is mutated and non-functional, the body has to rely on the other copy to regulate hunger. A single copy is not enough to signal satiation and such individuals end up eating too much and are at a risk of extreme hunger-driven obesity.
CRISPRa to 'The Rescue'A new system called CRISPRa (activation) was used by the research team at the UCSF lab of Jonathan Weissman, Professor of Cellular and Molecular Pharmacology to amplify the activity of the two obesity genes without actually making an edit.
CRISPRa does not actually edit or cut out parts of the genome. It can be programmed to target a particular DNA sequence and instead of using a molecular scissor it uses a volume control knob. It targets the specific sequence to increase the activity of the gene.
The research team developed CRISPRa systems to target sequences, which regulate the activity of SIM1 and MCR4 genes. They used a viral vector delivery system to induce CRISPRa constructs in the hunger control regions of brain in the genetically engineered mice which had just one functional copy of either SIM1 or MCR4. Mice which had a missing copy of the SIM1 gene received a CRISPRa injection at the age of 4 weeks.
The team also used a control group of mice with a single copy of either gene which did not receive the CRISPRa injection. They found the results surprising as mice that received the CRISPRa injection started producing more SIM1 or MCR4 as against those that did not receive the injection. These mice were able to maintain a healthy body weight over 10 months and more. The CRISPRa prevented the mice from developing extreme obesity.
Navneet Matharu, PhD and lead author of the new study at Ahituv lab said that CRISPRa can be used to increase the dosage of proteins produced by specific genes and this holds immense potential for curing diseases caused by a missing or mutated copy of genes. This system has a number of benefits as it does not actually edit the genome, but increases the dosage of insufficient proteins.
- CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency - (http://science.sciencemag.org/content/early/2018/12/12/science.aau0629)