Expanding fast! Best wishes to the Delas Lab! (and gorgeous color palette 😜💙)

Thanks also to Judith Zaugg (Sara Lobato and @kprummel.bsky.social) and Kyung-Min Noh ( @mattetrovato.bsky.social)‬ labs at @embl.org Heidelberg for hosting me during an awesome internship which brought some of the most exciting data!

📕Read the full preprint here: www.biorxiv.org/content/10.1...
Special thanks to my great PI and to the @radaiglesiaslab.bsky.social members at IBBTEC, specially to @sanchezgaya.bsky.social, whose work on the bioinformatics part of the project has been truly instrumental 💻📊📉⚡

By combining the ZIC2 degron, scMultiome and additional genomic data we stringently defined the ZIC2-dependent Gene Regulatory Network (GRN) during neural induction. We showed that the genes part of this GRN are particularly sensitive to ZIC2 dosage and, thus, might be implicated in HPE etiology.

ZIC2 acts as a temporal switchboard:
🧬It pioneers enhancers by opening chromatin
🔛Then activates them at just the right time
All to shape an anterior dorsal neural identity 🧠!

🤨Are we sure? What happens without ZIC2?
Brain patterning genes don’t turn on properly
➡️WNT signaling drops
➡️Neural progenitors skew toward more ventral fates
➡️Some even begin differentiating into neurons too early

🎭Act II: The Activator
Later, at day 5-6 (neural induction), ZIC2 flips the switch:
It activates a proportion of the enhancers it primed earlier.
This triggers expression of dorsal and midbrain fate genes, giving neural progenitors their regional identity. 🧠

ZIC2 doesn’t act randomly — it targets enhancers linked to patterning genes like:
➡️En1, Lmx1a/b, Pax2: playing crucial roles in midbrain and roof plate development.
➡️Wnt1, Wnt3a: core components of the WNT signaling pathway.

🎭 Act I: The Pioneer
At day 3 of differentiation (primed pluripotency), ZIC2 binds previously closed chromatin regions.
It opens them up — broadly “priming” putative regulatory elements, some linked to key neurodevelopmental genes.
📖A textbook case of pioneer transcription factor behavior.

But things change as mESC begin to differentiate into neural progenitors.
📉ZIC3 levels go down, and ZIC2 takes over📈
Now is when ZIC2’s real job begins — and it’s a two-act performance ✌️

The answer: ZIC3 steps in 💥
It is the most highly expressed ZIC family member in mESCs, and it adopts the starring role.
When we delete Zic3, pluripotency falls apart.
🧫 ZIC3 = the real main character (at this stage).

🔎This story starts with a mystery:
ZIC2 binds thousands of enhancers and promoters in pluripotent stem cells…
but when we knock it out, nothing happens. 🤷‍♀️
Cells look fine, gene expression is stable — no chaos.
🤯Why⁉️