- 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
- A new system CRISPRa (activation) to
amplify the activity of the two obesity genes without actually making an
- 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
at the University of San Francisco (UCSF).
extreme obesity is controlled by genes. Mutations in single copies of the genes
- SIM1 and MCR4 are mostly responsible for severe obesity in patients.
‘CRISPR can be used to prevent extreme obesity without actually editing the genome. CRISPRa (activation) regulation produced more SIM1 and MCR4 genes, which prevents from developing extreme obesity.’
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
Nadav Ahituv, PhD and
Professor of Bioengineering and Therapeutic Sciences, senior author of the
that if they could increase the dosage of the single normal
copy of the gene they would be able to prevent these serious genetic disorders.
CRISPRa to 'The Rescue'
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,
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.
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
- CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency - (http://science.sciencemag.org/content/early/2018/12/12/science.aau0629)