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bioRxiv · 10.64898/2026.10.21.760768

Micro-C-TALE: BAC-based targeted high-resolution measurement of 3D chromatin interactions

Golberg, A.·Golov, A. K.·Shemer, R.·Kaplan, N.
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Abstract

Chromosome conformation capture methods have greatly advanced our understanding of genome organization, but obtaining high-resolution interaction maps of selected genomic regions remains costly due to the sequencing requirements. Here, we introduce Micro-C-TALE, a new chromosome conformation capture method that combines Micro-C, which uses micrococcal nuclease to improve the resolution and sensitivity of chromatin interaction measurements, and C-TALE, which uses probes generated from bacterial artificial chromosomes (BACs) for targeted enrichment. This combination enables the generation of high-resolution interaction maps without requiring custom synthesis of capture oligonucleotides. We applied Micro-C-TALE to a 214 kb region in human HAP1 cells, obtaining detailed interaction maps with approximately 5-6 million sequenced read pairs. Compared with published genome-wide Micro-C data, Micro-C-TALE yielded a higher amount of informative interactions within the targeted region despite ~550-fold lower sequencing depth. To evaluate the sensitivity of the method to fine-scale changes in genome organization, we introduced a heterozygous CTCF binding site into the targeted region using CRISPR-Cas9. Comparing Micro-C-TALE to the restriction enzyme-based C-TALE, we found Micro-C-TALE yielded a ~5-fold higher fraction of informative reads and detected novel CTCF-mediated point interactions associated with the inserted CTCF site, which were barely discernible using C-TALE. Our results demonstrate that Micro-C-TALE provides a flexible and cost-effective approach for targeted high-resolution measurement of chromatin interactions, facilitating the investigation of fine-scale genome organization and its response to genetic perturbations.

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Golberg, A., Golov, A. K., Shemer, R., Kaplan, N.. 2026-10-23. Micro-C-TALE: BAC-based targeted high-resolution measurement of 3D chromatin interactions. https://doi.org/10.64898/2026.10.21.760768

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