PT - JOURNAL ARTICLE AU - Fatima S. Ugur AU - Mark J. S. Kelly AU - Danica Galonić Fujimori TI - X-linked intellectual disability mutations alter the conformational state of a histone demethylase’s sensing of chromatin AID - 10.1101/2022.01.13.476263 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.01.13.476263 4099 - http://biorxiv.org/content/early/2022/01/14/2022.01.13.476263.short 4100 - http://biorxiv.org/content/early/2022/01/14/2022.01.13.476263.full AB - The H3K4me3 chromatin modification, a hallmark of promoters of actively transcribed genes, is dynamically removed by the KDM5 family of histone demethylases. The KDM5 demethylases have a number of accessory domains, two of which, ARID and PHD1, lie within the catalytic domain. KDM5C, which has a unique role in neural development, harbors a number of mutations adjacent to its accessory domains that cause X-linked intellectual disability (XLID). The roles of these accessory domains remain unknown, limiting an understanding of how XLID mutations affect KDM5C activity. We find that while the ARID and PHD1 domains are required for efficient nucleosome demethylation, the PHD1 domain alone has an inhibitory role in KDM5C catalysis. We further find that binding of the H3 tail to PHD1 is coupled to the recognition of linker DNA by KDM5C. Our data suggests a model in which the PHD1 domain regulates DNA recognition by the ARID domain based on available substrate cues. In this model, recognition of distinct chromatin features is coupled to a conformational rearrangement of the ARID and PHD1 domains, which in turn modulates the positioning of the catalytic domain for efficient nucleosome demethylation. Importantly, we find that XLID mutations adjacent to the ARID and PHD1 domains alter the conformational state of these domains to enhance DNA binding. This results in the loss of specificity in chromatin recognition by KDM5C and renders catalytic activity sensitive to inhibition by linker DNA. Our findings suggest a unifying model by which XLID mutations alter chromatin recognition and enable euchromatin-specific dysregulation of demethylation by KDM5C.Competing Interest StatementThe authors have declared no competing interest.