High-order enhancer hubs buffer allelic regulatory variation through kinetic compensation
- 1Washington University in St. Louis
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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BibTeX
@misc{tan2026highorder,
title = {{High-order enhancer hubs buffer allelic regulatory variation through kinetic compensation}},
author = {J. Tan and M. Sentmanat and Y. Wu and C. Peng and C. Fronick and C. Markovic and X. Cui and R. Fulton and R. Head and T. Wang and Y. Sun},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.14.750771},
url = {https://www.biorxiv.org/content/10.64898/2026.09.14.750771v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - High-order enhancer hubs buffer allelic regulatory variation through kinetic compensation
AU - J. Tan
AU - M. Sentmanat
AU - Y. Wu
AU - C. Peng
AU - C. Fronick
AU - C. Markovic
AU - X. Cui
AU - R. Fulton
AU - R. Head
AU - T. Wang
AU - Y. Sun
PY - 2026
DA - 2026/09/14
PB - bioRxiv
DO - 10.64898/2026.09.14.750771
UR - https://www.biorxiv.org/content/10.64898/2026.09.14.750771v1
AB - 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.
ER -