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Background: Kabuki syndrome (KS) is a rare developmental disorder characterised by multiple congenital anomalies and intellectual disability. UTX (ubiquitously transcribed tetratricopeptide repeat, X chromosome), which encodes a histone demethylase, is one of the two major pathogenic risk genes for KS. Although intellectual disability is a key phenotype of KS, the role of UTX in cognitive function remains unclear. Currently, no targeted therapies are available for KS., Aims: This study aimed to investigate how UTX regulates cognition, to explore the mechanisms underlying UTX dysfunction and to identify potential molecular targets for treatment., Methods: We generated UTX conditional knockout mice and found that UTX deletion downregulated calmodulin transcription by disrupting H3K27me3 (trimethylated histone H3 at lysine 27) demethylation., Results: UTX -knockout mice showed decreased phosphorylation of calcium / calmodulin-dependent protein kinase II, impaired long-term potentiation and deficit in remote contextual fear memory. These effects were reversed by an Food and Drug Administration-approved drug desipramine., Conclusions: Our results reveal an epigenetic mechanism underlying the important role of UTX in synaptic plasticity and cognitive function, and suggest that desipramine could be a potential treatment for KS., Competing Interests: None declared., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: This study aimed to investigate the effect and mechanism of Klotho in lipopolysaccharide (LPS)-induced inflammation injury in HK-2 cells., Methods: We established LPS-induced inflammation injury model in HK-2 cells. The LPS-induced HK-2 cells were transfected with pc-Klotho, pcDNA3.1, siKlotho or siNC. Cell viability, apoptosis and reactive oxygen species (ROS) level were detected by MTT assay, Annexin V-FITC/PI Apoptosis Detection kit and 2,7-dichlorofluorescein diacetate, respectively. The levels of inflammatory factors and the expressions of proteins related to Wnt and nuclear factor-κB (NF-κB) signaling pathway were detected by RT-qPCR and western blotting, respectively., Results: Compared with cells transfected with pcDNA 3.1, cell viability was remarkably increased and cell apoptosis rate was decreased in LPS-induced cells with pc-Klotho (p < 0.05). Conversely, LPS-induced cells with siKlotho showed lower cell viability and higher cell apoptosis rate than cells with siNC (p < 0.05). The levels of ROS, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) was significantly reduced in LPS-induced cells with pc-Klotho compared with cells with pcDNA3.1 (p < 0.05). Consistently, LPS-induced cells with siKlotho showed increased levels of ROS, TNF-α and IL-6 compared with cells with siNC (p < 0.05). Wnt signaling pathway related protein Wnt3a and NF-κB signaling pathway related to proteins p-IκBα were significantly down-regulated in LPS-induced cells with pc-Klotho compared with cells with pcDNA3.1, while up-regulated in LPS-induced cells with pc-Klotho compared with cells with pcDNA3.1 (p < 0.05)., Conclusions: Klotho may play an inhibiting role in LPS-induced inflammation injury by inhibiting NF-κB and Wnt signaling pathways in HK-2 cells.