Transition paths across the EMT landscape are dictated by network logic. A 🧵 on the perils of ignoring logic in ODE models of gene regulatory networks (GRNs) 🌟 also read on if you like: EMT, bifurcations, multistability, or Waddington-esque landscapes www.biorxiv.org/content/10.1... - ThreadSky

adamlmaclean.bsky.social • 77 days ago

Transition paths across the EMT landscape are dictated by network logic.

A 🧵 on the perils of ignoring logic in ODE models of gene regulatory networks (GRNs)

🌟 also read on if you like: EMT, bifurcations, multistability, or Waddington-esque landscapes

https://www.biorxiv.org/content/10.1101/2024.12.03.626660

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adamlmaclean.bsky.social•77 days ago

When you turn a GRN into an ODE model you make a choice of logic*: do effects combine multiplicatively or additively? (AND vs OR logic)

(*even if you may not realize it; ODEs make the choice less explicit than e.g. Boolean network modeling)

adamlmaclean.bsky.social•77 days ago

Can we decide what network logic to use a priori?   Typically: no, not without specific measurements of the network of interest.

Target genes display both additive and multiplicative effects, as neat exps from @arjunraj.bsky.social lab have shown

https://elifesciences.org/articles/59388

adamlmaclean.bsky.social•77 days ago

Tristable EMT can be described by a three-node network. Thus! an ideal system to test the role of logic in determining phenotypes

ALSO competing ⚔️ models of EMT in the literature are constructed with different logic..

OR: Tian et al. 10.1016/j.bpj.2013.07.011
AND: Lu et al. 10.1073/pnas.1318192110

adamlmaclean.bsky.social•77 days ago

So we built AND & OR versions of the three-node EMT network to study the effects of perturbing various interactions: direct activation of B, vs indirect activation of B (aka inhibition of A).

adamlmaclean.bsky.social•77 days ago

We discovered that the choice of logic (AND vs OR) leads to divergent and opposing phenotypes

For AND logic
👉 increasing direct activation of B destabilizes the intermediate state

👉 whereas increasing the inhibition of miR-200 destabilizes the epithelial state, leading to earlier initiation of EMT

adamlmaclean.bsky.social•77 days ago

For OR logic, the converse is true. Choice of logic flips the importance of network regulations and thus completely changes inferences one draws!

We undertake analysis of a large parameter space of tristable EMT models to show that these results hold true generally, also for alt model formulations.

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