Exploring multi-level microbial interactions from individual 3D genomes to community networks

Microbial communities interact with their hosts through complex genomic networks that influence ecosystem stability and disease progression. Here, we present FindMeta3D, a computational framework that simultaneously identifies microbial three-dimensional (3D) genome structures and cross-domain interaction networks. Applying this approach to 528 Hi-C samples, we resolved 3D genome structures of 344 microbial species, revealing five evolutionarily conserved chromatin folding patterns linked to intrinsic sequence features. Further analyses demonstrated distinct microbial-host interaction preferences and identified functional interaction hotspots that are critical for infection. Experimental deletion of such hotspots in the EBV genome resulted in significant infection defects, demonstrating their essential role in viral infectivity. Additionally, we constructed the first Cross-domain Microbial Interaction Network (CMIN), which uncovered pathogen-specific subnetworks and demonstrate dramatic restructuring of gut microbial communities in neutropenic patients, including enhanced Klebsiella-phage interactions. Subnetwork analysis identified potential phage therapy targets, such as Klebsiella phage ST16-OXA48phi5.4. These findings provide fundamental insights into microbial 3D genomics and establish FindMeta3D as a powerful platform for studying microbial genome structure and communities and developing antimicrobial strategies.