Compaction of chromatin domains regulates target search times of proteins

Shuvadip Dutta, Adarshkrishnan Rajakumar, Ranjith Padinhateeri and Mithun K Mitra

PLOS Computational Biology, 2026, vol. 22, issue 1, 1-25

Abstract: Protein molecules must efficiently locate specific DNA sequences within the densely packed chromatin of the cell nucleus. We investigate how the spatial organisation of chromatin, specifically into Topologically Associating Domains (TADs), fundamentally affects this search process. Using exact analytical theory and simulations of different models of chromatin, we show that target search within compact, highly connected chromatin domains can leverage intersegmental jumps to significantly decrease search times. Further, we show that there exists an optimal degree of polymer compaction that minimizes the search time for proteins to find their targets. We show that for highly folded domains, rather than bulk diffusion, intersegmental transfers – jumping between chromatin segments that are close together in space – drive the optimal search process. Remarkably, when we analyse 8,355 TAD structures across the human genome, we find that their natural connectivity matches with the theoretical optimum predicted by our model. The structural organisation within TADs significantly reduces protein search times far beyond what is achievable through classical facilitated diffusion. In essence, our work suggests that packaging of chromatin inside the nucleus has implications beyond spatial organisation, and is also intricately linked to dynamics of proteins inside the nuclear environment.Author summary: Inside the dynamic world of cells, proteins must quickly locate specific sequences on chromatin to bind and execute their functions. In this manuscript, we explore how proteins find their targets within densely packed chromatin—the combination of DNA and proteins that form chromosomes. Using exact analytic theory and computer simulations, we studied how the three-dimensional organisation of chromatin—especially into structures called Topologically Associating Domains (TADs)—affects the ability of proteins to locate their targets. We show that the topology of chromatin helps proteins search for their targets by jumping between spatially adjacent chromatin segments. Remarkably, we show that chromatin has an optimal connectivity which minimises the search time to locate the target. We then analysed experimental data for thousands of TADs from human chromosomes to show that the natural organisation of TADs falls within this optimum region that minimises search times. This suggests that chromatin topology plays a crucial role not only in spatial organisation, but also enables faster protein search and hence aids gene regulation.

Date: 2026
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1013843

DOI: 10.1371/journal.pcbi.1013843

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