HNF1β bookmarking involves Topoisomerase 1 activation and DNA topology relaxation in mitotic chromatin

HNF1β (HNF1B) is a transcription factor frequently mutated in patients with developmental renal disease. It binds to mitotic chromatin and reactivates gene expression after mitosis, a phenomenon referred to as bookmarking. Using a crosslinking method that circumvents the artifacts of formaldehyde, we demonstrate that HNF1β remains associated with chromatin in a sequence-specific way in both interphase and mitosis. We identify an HNF1β-interacting protein, BTBD2, that enables the interaction and activation of Topoisomerase 1 (TOP1) exclusively during mitosis. Our study identifies a shared microhomology domain between HNF1β and TOP1, where a mutation, found in “maturity onset diabetes of the young” patients, disrupts their interaction. Importantly, HNF1β recruits TOP1 and induces DNA relaxation around HNF1β mitotic chromatin sites, elucidating its crucial role in chromatin remodeling and gene reactivation after mitotic exit. These findings shed light on how HNF1β reactivates target gene expression after mitosis, providing insights into its crucial role in maintenance of cellular identity. [Display omitted] •HNF1β mitotic site binding is preserved with a specific methanol/formaldehyde ChIP•BTBD2, an HNF1β partner, mediates mitosis-specific interaction with TOP1•HNF1β recruits TOP1 and induces DNA relaxation around bookmarked HNF1β sites•An HNF1β mutation, found in MODY patients, disrupts the interaction with TOP1 Bagattin et al. developed a ChIP methodology that strongly improves the identification of HNF1β-bound mitotic regions. They demonstrate that HNF1β remains associated with mitotic chromatin and recruits TOP1 on bookmarked sites in order to resolve DNA topological constraints. An HNF1β mutation, found in MODY patients, prevents the interaction with TOP1.