Post-translational modifications of histones affect a variety of chromatin template-based events, including transcription, replication, and DNA repair. Chromatin dysregulation has emerged as a major contributor to neurodevelopmental and psychiatric disorders.
Intellectual disability (ID) is a prevalent brain disorder, affecting 1%–2% of the total population, and represents a major unmet medical need worldwide. ID is defined as limitations in both adaptive behavior and intellectual functioning. Despite the identification of genetic variations associated with different forms of ID, the cellular and molecular etiology of ID remains poorly understood.
KDM5C (also known as SMCX and JARID1C) is an X-linked gene whose protein product belongs to a subfamily of JmjC domain histone demethylases that mediate demethylation of histone H3K4me2/3. Human genetic studies identified an association between KDM5C mutations and X-linked ID (XLID), estimated to account for 0.7%–2.8% of all XLID cases). Patient mutations in KDM5C include nonsense and missense mutations; all patient missense mutations tested compromise KDM5C’s enzymatic activity, suggesting a loss-of-function disease mechanism.
Interestingly, KDM5C has been implicated in other neurological abnormalities, including ID caused by mutations in ARX, autism spectrum disorder (ASD), and cerebral palsy, suggesting that it may be a critical regulator of brain development and function. KDM5C is ubiquitously expressed, with the highest levels observed in brain and skeletal muscle in huma. In the mouse brain, Kdm5c is broadly expressed in areas relevant to cognitive and emotional behaviors such as the prefrontal cortex, hippocampus, and amygdala . However, the role of KDM5C in the central nervous system remains elusive.
Researchers report that disruption of the mouse Kdm5c gene recapitulates adaptive and cognitive abnormalities observed in XLID, including impaired social behavior, memory deficits, and aggression.
Kdm5c-knockout brains exhibit abnormal dendritic arborization, spine anomalies, and altered transcriptomes. In neurons, Kdm5c is recruited to promoters that harbor CpG islands decorated with high levels of H3K4me3, where it fine-tunes H3K4me3 levels.
Kdm5c predominantly represses these genes, which include members of key pathways that regulate the development and function of neuronal circuitries. In summary, our mouse behavioral data strongly suggest that KDM5C mutations are causal to XLID.
Furthermore, these findings suggest that loss of KDM5C function may impact gene expression in multiple regulatory pathways relevant to the clinical phenotypes.
http://www.cell.com/cell-reports/abstract/S2211-1247(15)01547-8
A Mouse Model of X-linked Intellectual Disability
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