Test the mechanistic basis of transcriptional variance asymmetry

Determine whether differences in chromatin accessibility or co-activator availability explain why psilocybin-induced upregulation is more variable across individuals than psilocybin-induced downregulation.

Background

The delta expression encoder identifies a significant asymmetry in inter-individual transcriptional variability: genes classified as DOWN have lower variance across animals than genes classified as UP. The paper proposes that constitutively active repressor complexes may respond more uniformly to receptor stimulation, whereas activating programs may depend more strongly on individual chromatin accessibility, co-activator availability, or prior activity state.

This mechanistic explanation is explicitly presented as biologically plausible but unresolved because the study does not test it against chromatin-accessibility or co-activator measurements. Establishing whether these molecular factors account for the observed asymmetry would help distinguish a genuine regulatory mechanism from an alternative explanation based on the model or dataset.

References

One plausible biological account is that repressive transcriptional programs are often executed by constitutively active repressor complexes that respond uniformly to receptor stimulation, while activating programs may depend more on individual differences in chromatin accessibility, co-activator availability, or prior activity state. This account is biologically plausible and consistent with general principles of transcriptional regulation, but it has not been directly tested against chromatin or co-activator data here and should be read as a hypothesis motivated by this result, not a finding it establishes.

— A Transformer-Based Delta Expression Encoder for Psilocybin Transcriptional Response: Architecture, Representations, and Biological Validation  (2609.08165 - Jayakumar, 8 Sep 2026) in Results, Section 2, paragraph discussing the biological account of DOWN/UP variance asymmetry