Laura De Conti,
Hyung Chul Kim,
Narjes Rohani,
@chundru.bsky.social
Laura Watts,
@ruebenadawes.bsky.social
@yuyangchen.bsky.social
@alextremophile.bsky.social
Michael Griffiths,
Sam Scott,
Rosemary Bamford,
Jonathan Mill,
@carolinefwright.bsky.social
Marco Baralle,
@stephansanders.bsky.social

Thank you *very much* to my co-authors, supervisors, and funders for your contributions, belief and support 🙏
@wellcometrust.bsky.social
@ndm.ox.ac.uk
@idrm.ox.ac.uk
@icgeb.bsky.social
@nickywhiffin.bsky.social

We also increased expression of a 5th gene by excluding additional uORFs downstream of the ‘skippable’ exon - highlighting the importance of redundancy between these features ⚠️ But, we also show uORFs can also work additively, such that you get an incremental boost each time you remove one! 💡

We investigated 6 genes in the lab associated with NDD 🧠. Using a luciferase assay, we found the expression of 4/6 genes increased by excluding a uORF-containing exon! 📈 Laying the groundwork for SSO investigations 🔎

Outcome?
We wrote a pipeline to identify genes:
1. associated with conditions caused by loss of function in one allele,
2. with uORFs,
3. which could be removed by skipping out a 5'UTR exon (using an RNA therapeutic which alters splicing or CRISPR).
✨ And found >50! ✨

How?
By excluding repressive features, uORFs, from mRNA.
uORFs make ribosomes begin translation early in the 5’UTR 🏃‍➡️🟢——>🛑
Afterwards, ribosomes need some distance to reset 😴, and might leave 🙅, This leads to lower translation of the main coding sequence.

Most approaches to increase gene expression are contextually unique, but this method can be applied to multiple genes! 🙌

Why?
People (like me!) can have genetic conditions because one of their two copies of a gene isn’t working.
🧬✅ 🧬✅ = 😊
🧬✅ 🧬❌ = 🙁
We look at a new way of boosting the output of the remaining functional copy.
🧬✅ ✅ 🧬❌ = 😊