Chromatin Sensing by the Auxiliary Domains of KDM5C Regulates Its Demethylase Activity and Is Disrupted by X-linked Intellectual Disability Mutations

•Dysregulation of KDM5C in X-linked intellectual disability is poorly understood.•ARID domain of KDM5C aids nucleosome demethylation, while PHD1 domain inhibits it.•Unstructured ARID-PHD1 linker impacts nucleosome and flanking DNA recognition.•XLID mutations enhance nucleosome binding and enable inhibition by linker DNA.•XLID mutations relieve inhibition of KDM5C that modulates nucleosome demethylation.