Loss of Kdm5c Causes Spurious Transcription and Prevents the Fine-Tuning of Activity-Regulated Enhancers in Neurons

Abstract

Summary During development, chromatin-modifying enzymes regulate both the timely establishment of cell type-specific gene programs and the coordinated repression of alternative cell fates. To dissect the role of one such enzyme - the intellectual disability-linked lysine demethylase 5C gene (Kdm5c) – in the developing and adult brain, we conducted parallel behavioral, transcriptomic and epigenomic studies in Kdm5c null and forebrain-restricted inducible knockout mice. Together, genomic analyses and functional assays demonstrate that Kdm5c plays a critical role as a repressor responsible for the developmental silencing of germ line genes during cellular differentiation, and in fine-tuning activity-regulated enhancers during neuronal maturation. Although the importance of these functions declines after birth, Kdm5c retains an important genome surveillance role preventing the incorrect activation of non-neuronal and cryptic promoters in adult neurons.

A Drosophila Model of Intellectual Disability Caused by Mutations in the Histone Demethylase KDM5

“…The KDM5 A512P mutation did not affect protein levels, distinguishing this model from the previous mouse KDM5C knockout model (Iwase et al, 2016; Scandaglia et al, 2017), and caused dramatic changes to the neuronal transcriptome and to the cognitive abilities of the fly. kdm5 A512P mutants behaved indistinguishably from the demethylase-inactive strain ( kdm5 JmjC* ), suggesting that loss of enzymatic activity is the primary defect associated with this mutation.…”

“…A major step forward in this goal came from the generation of a KDM5C knockout mouse strain designed to model the effects of nonsense and other mutations expected to result in a complete loss of KDM5C gene function (Iwase et al, 2016; Scandaglia et al, 2017). KDM5C knockout mice had defective learning, aberrant social interactions, hyperreflexia, and propensity for seizures.…”

The Sex Chromosome Hypothesis of Schizophrenia: Alive, Dead, or Forgotten? A Commentary and Review

“…Mutations in histone H3 methylation have been shown to be involved in several disorders of intellectual disability. Additionally, it has been found to be involved in the transcription of genes related to neural plasticity and neural maturation [66].…”

Gene regulatory mechanisms underlying sex differences in brain development and psychiatric disease

“…Mutations in KDM5C have been implicated in a variety of neurodevelopmental disorders, including intellectual disability, ASD, and cerebral palsy . Mice lacking Kdm5c display increased aggression, decreased anxiety, impaired motor coordination, and decreased dendritic arborization in the amygdala, although these phenotypes are dramatically reduced with a forebrain‐specific deletion in adulthood . This finding provides evidence that these enzymes have distinct genomic targets in specific cellular or developmental contexts.…”