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bioRxiv · 10.64898/2026.11.01.763377

A compact motif vocabulary is differentially interpreted across human cell types

Shen, S.·Wang, W.
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Abstract

How a common genome generates diverse human cell types may depend less on distinct cis-regulatory vocabularies than on context-dependent use of a shared one. We have developed CNN-CR, an interpretable neural network that learns regulatory motifs while predicting gene expression across 116 human biosamples. Promoter regulation proves highly compressible: dozens of recurrent motif families retain most of the predictive information of much larger cell-type-specific vocabularies and generalize to cellular contexts excluded from their discovery. These motifs are conserved at their binding sites and enriched at fine-mapped regulatory variants. Cellular context acts at two levels: chromatin state gates which motif instances are available for regulatory use, whereas reader identity determines how accessible motifs are interpreted. ChIP-seq data reveal frequent shifts in reader occupancy across cell types, and genome-scale perturbations support corresponding context-dependent reader functions. Thus, regulatory diversity can emerge through differential access to and interpretation of a compact shared DNA vocabulary.

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Shen, S., Wang, W.. 2026-11-03. A compact motif vocabulary is differentially interpreted across human cell types. https://doi.org/10.64898/2026.11.01.763377

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