High-order enhancer hubs buffer allelic regulatory variation through kinetic compensation

Authors

Tan, J., Sentmanat, M., Wu, Y., Peng, C., Fronick, C., Markovic, C., Cui, X., Fulton, R., Head, R., Wang, T., Sun, Y.

Abstract

Diploid genomes carry millions of heterozygous variants in cis-regulatory DNA, yet most genes produce similar RNA output from two parental alleles. How this balance is maintained is unclear. We developed Nanopore-HiChIP, a long-read method that maps high-order enhancer hubs on each haplotype. Over half of these enhancer hubs differ in chromatin architecture and transcription-factor occupancy between homologous chromosomes, but their target genes show substantially lower rates of allele-specific expression than genes lacking hub regulation. Single-cell kinetic modeling shows that burst frequency and burst size change in opposite directions, thereby preserving balanced transcriptional output. This hub-mediated kinetic buffering is enriched at haploinsufficient genes and coincides with smaller effects of expression quantitative trait loci. Enhancer hubs therefore absorb allelic regulatory variation through kinetic compensation, protecting dosage-sensitive transcription.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 22 Sep 2026.

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