Work from Professor Yang Shi’s research team both in the Boston Children’s Hospital, Harvard Medical School and Oxford has shed new light on KDM5C mutation-associated intellectually disability and advanced the general understanding of memory and anxiety formation with the identification of Wnt functioning in a transient nature to impact long-lasting cognitive function.
Neurodevelopment is an orchestrated process where progenitors and neurons emerge during development in a rigorously coordinated temporal and spatial order. Mutations on the histone H3 lysine 4 di- and tri-methyl specific demethylase KDM5Care found in patients with intellectual disability, autism spectrum disorder, cerebral palsy and Huntington’s disease. Therefore, KDM5C is an important regulator to study the neurodevelopmental causes of cognitive dysfunction.
Violetta Karwacki-Neisius and co-workers performed detailed cellular, transcriptomic and chromatin studies in human patient-derived induced pluripotent stem cells as well as behavioural studies and identified KDM5C as a safeguard to ensure that neurodevelopment occurs at an appropriate timescale. Specifically, the researchers identified a critical developmental window in KDM5C mutant cells with an inefficient and delayed entry of primary progenitors into the intermediate progenitor stage, and consequently into neurons. Mechanistically, Karwacki-Neisius et al., elucidated that major components of the Wnt/β-catenin pathway are direct targets of KDM5C and are upregulated in mutant cells. Specific and transient treatments with Wnt inhibitors in the identified window made KDM5C mutant cells indistinguishable from corrected cells on the cellular level. Conversely, corrected cells treated with recombinant Wnt3a resembled mutant cells. Comprehensive examination of the global transcriptomic and epigenetic landscapes confirmed a remarkable sensitivity to Wnt modulation in the identified window, showcasing a switching between transcriptomic and epigenetic states depending upon the direction of the Wnt modulation
So far, no treatments for KDM5C mutation associated ID were available as no therapeutic targets or window of clinical perturbations have been identified. This fundamental discovery by Yang Shi’s research team could therefore aid treatments in patients affected with intellectual disability.
More details can be found in the Nature article.