Chromatin priming and co-factor availability shape lineage response to the neuronal pioneer factor ASCL1 in pluripotency

The spotLight (above) is part of our ‘preprints by preLighters’ series, where we highlight exciting preprints authored by members of the preLights community.

Transcript:

I’m Jethro Lundie-Brown. I’m a preLighter and I’ve been working at Cambridge Stem Cell Institute on how transcription factors control gene expression and how this affects cell identity.

In our recent preprint, we’re particularly interested in a transcription factor called ASCL1, which makes neurons. And it’s so good at making neurons in development and in vitro reprogramming strategies that when cells express ASCL1, they will undergo neuronal differentiation.

ASCL1 does this by what’s called pioneering activity where it binds its target genes and promotes their chromatin accessibility to drive gene expression. What surprised us most was that when we activated ASCL1 in the embryonic stem cells, we found that actually these cells didn’t undergo neuronal differentiation and they responded quite differently. And this raised the question of why? Why does this happen?

There’s an idea that embryonic stem cells are a blank canvas capable of giving rise to any cell in the body. And actually what we found is that the chromatin has to be primed in order to respond to transcription factors in the appropriate way. By extension this shows that ASCL1 actually acts in a context-specific manner and this is not what the pioneer model would predict.

We found that the barrier to differentiation could be lowered by providing additional transcription factors in combination with ASCL1 such that the embryonic stem cells – where they didn’t respond to ASCL1 alone – could be encouraged to differentiate towards neurons by providing additional co-acting transcription factors.

The combinatorial approach of transcription factor activity raises interesting questions about how these transcription factors work in development to specify cell fates. And it also opens the avenue for combinatorial reprogramming strategies where we can work out the modular logic of which transcription factors act together to give rise to a particular cell of interest.

If you’d like to know more, our preprints available on bioRxiv. The link will be in the description below. So, please look it up and give it a read.

Link to preprint: https://www.biorxiv.org/content/10.64898/2026.03.19.712999v2

Tags: ascl1, cell fate, chromatin, developmental biology, gene regulation, genetics, neuronal differentiation, neuroscience, pluripotency, stem cells, transcription factors

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