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.