A haplotype-resolved view of human gene regulation

Vollger, M. R.; Swanson, E. G.; Neph, S. J.; Ranchalis, J.; Munson, K. M.; Ho, C.-H.; Sedeno-Cortes, A. E.; Fondrie, W. E.; Bohaczuk, S. C.; Mao, Y.; Parmalee, N. L.; Mallory, B. J.; Harvey, W. T.; Kwon, Y.; Garcia, G. H.; Hoekzema, K.; Meyer, J. G.; Cicek, M.; Eichler, E. E.; Noble, W. S.; Witten, D. M.; Bennett, J. T.; Ray, J. P.; Stergachis, A. B.

doi:10.1101/2024.06.14.599122

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bioRxiv · 10.1101/2024.06.14.599122

A haplotype-resolved view of human gene regulation

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Abstract

Diploid human cells contain two non-identical genomes, and differences in their regulation underlie human development and disease. We present Fiber-seq Inferred Regulatory Elements (FIRE) and show that FIRE provides a more comprehensive and quantitative snapshot of the accessible chromatin landscape across the 6 Gbp diploid human genome, overcoming previously unrecognized biases in existing regulatory element catalogs. FIRE enables comprehensive detection of haplotype-selective chromatin accessibility (HSCA), exposing novel imprinted elements lacking underlying parent-of-origin CpG methylation differences, and gene regulatory modules that permit genes to escape X chromosome inactivation. We uncover that the human leukocyte antigen (HLA) locus harbors the most HSCA in immune cells, where we resolve specific transcription factor (TF) binding events disrupted by disease-associated variants. Finally, we demonstrate that the regulatory landscape of a cell is littered with autosomal somatic chromatin epimutations that are propagated by clonal expansions to create mitotically stable and non-genetically deterministic chromatin alterations.

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Vollger, M. R., Swanson, E. G., Neph, S. J., Ranchalis, J., Munson, K. M., Ho, C.-H., Sedeno-Cortes, A. E., Fondrie, W. E., Bohaczuk, S. C., Mao, Y., Parmalee, N. L., Mallory, B. J., Harvey, W. T., Kwon, Y., Garcia, G. H., Hoekzema, K., Meyer, J. G., Cicek, M., Eichler, E. E., Noble, W. S., Witten, D. M., Bennett, J. T., Ray, J. P., Stergachis, A. B.. 2024-06-16. A haplotype-resolved view of human gene regulation. https://doi.org/10.1101/2024.06.14.599122

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