Many disease-causing DNA changes (variants) within gene regulatory elements might be found to play a role in multiple tissues or organs simultaneously (i.e., pleiotropic effect) to drive a convergent disease phenotype, contrary to the belief that regulatory elements are highly tissue-specific.

Example: Multiple variants control the expression of IRX3 and IRX5 genes in both human adipose tissue and brain, the coordinated effects of which (less thermogenesis and more feeding behavior) result in obesity.

https://pubmed.ncbi.nlm.nih.gov/34083488/

Context, please…

DNA changes that are either inherited or newly emerged may cause genetic diseases or conditions (for example, diabetes). Many change the sequences of genes, but most don’t. They instead change the sequences of gene regulatory elements.

Regulatory what?

Regulatory elements, such as promoter and enhancers, work coordinately to control gene expression. Think about the lights in your home. Every room has lights, but you might want a different brightness and hue for your bedroom vs your living room. Likewise, regulatory elements help ‘customize’ the activity of a given gene for different tissues in your body.

The popular belief is that regulatory elements are tissue-specific. That is, each tissue has its unique set of regulatory elements for a gene. But the notion described above that regulatory elements might be shared between tissues, and that the same DNA change might affect multiple tissues in such a way that the coordinated effects result in the same disease outcome is both unexpected and intriguing.

Credit

Dr. Débora Sobreira’s work in the lab of Marcelo Nóbrega.

In the coming years, CRISPR will democratize therapeutic genome editing for n=1 genetic diseases. These efforts will be sponsored by academic institutions and nonprofits, as opposed to companies, because they won’t be profitable.

Explainers

n=1 genetic diseases: Ones that are so rare that there is likely only one, or up to a handful, cases diagnosed across the globe.

Why democratizing genome editing is important: Since developing a treatment or cure for this kind of diseases only benefits so few people, there isn’t enough financial incentive for companies. To help the often devastated patients, it’s up to the governments, academic institutions, and nonprofits to shoulder the cost of the development of these highly specific therapies.

Credit

Inspired by Dr. Fyodor Urnov’s keynote presentation at World CRISPR Day 2021. The recording can be found here:

https://worldcrisprday.com/s/agenda97/home

In 5-10 years, CRISPRa will treat or cure 10s to 100s of genetic diseases caused by haploinsufficiency in human patients.

Example: SIM1 in extreme obesity.

https://www.science.org/doi/10.1126/science.aau0629?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

Explainers

CRISPRa: CRISPRa, a technology derived from CRISPR, works like a light dimmer that can turn up the expression level of a given gene.

Haploinsufficiency: Like matcha ice cream on a hot summer day, sometimes having one functional copy of a gene is just not enough for your body. You need two. Close to 1000 genes in the human genome (out of total ~20,000) are predicted to work this way.

Credit

Inspired by work from Dr. Nadav Ahituv’s lab at UCSF.