Deaminase-mediated chromatin accessibility profiling with single-allele resolution

Yu, T.; Li, Z.; Gibbs, E.; Iwase, R.; Francoeur, M. J.; Phan, Q. v.; Zhao, J.; Rosin, J.; Cole, P. A.; Pinello, L.; Sherwood, R. I.

doi:10.1101/2024.12.17.628768

bioRxiv · 10.1101/2024.12.17.628768

Deaminase-mediated chromatin accessibility profiling with single-allele resolution

Yu, T.·Li, Z.·Gibbs, E.·Iwase, R.·Francoeur, M. J.·Phan, Q. v.·Zhao, J.·Rosin, J.·Cole, P. A.·Pinello, L.·Sherwood, R. I.

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Abstract

Binding of transcription factors (TFs) at gene regulatory elements controls cellular epigenetic state and gene expression. Current genome-wide chromatin profiling approaches have inherently limited resolution, complicating assessment of TF occupancy and co-occupancy, especially at individual alleles. In this work, we introduce Accessible Chromatin by Cytosine Editing Site Sequencing with ATAC-seq (ACCESS-ATAC), which harnesses a double-stranded DNA cytosine deaminase (Ddd) enzyme to stencil TF binding locations within accessible chromatin regions. We optimize bulk and single-cell ACCESS-ATAC protocols and develop computational methods to show that the increased resolution compared with ATAC-seq improves the accuracy of TF binding site prediction. We use ACCESS-ATAC to perform genome-wide allelic occupancy and co-occupancy imputation for 64 TFs each in HepG2 and K562, revealing that the propensity of a majority of TFs to co-occupy nearby motifs oscillates with a period approximating the helical turn of DNA. Altogether, ACCESS-ATAC expands the resolution and capabilities of bulk and single-cell epigenomic profiling.

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Yu, T., Li, Z., Gibbs, E., Iwase, R., Francoeur, M. J., Phan, Q. v., Zhao, J., Rosin, J., Cole, P. A., Pinello, L., Sherwood, R. I.. 2024-12-20. Deaminase-mediated chromatin accessibility profiling with single-allele resolution. https://doi.org/10.1101/2024.12.17.628768

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