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

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

doi:10.64898/2026.09.14.750771

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bioRxiv · 10.64898/2026.09.14.750771

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

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

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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.

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Tan, J., Sentmanat, M., Wu, Y., Peng, C., Fronick, C., Markovic, C., Cui, X., Fulton, R., Head, R., Wang, T., Sun, Y.. 2026-09-21. High-order enhancer hubs buffer allelic regulatory variation through kinetic compensation. https://doi.org/10.64898/2026.09.14.750771

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