Autism-associated mutations in Kdm6b affect its role as a chromatin regulator in brain development

ABSTRACT: The regulation of gene expression in the developing brain is coordinated by changes in chromatin regulation. Chromatin regulation involves the deposition and removal of molecular modifications on the histone proteins that give structure to and control the function of genomic DNA. The trimethylation of histone H3 at lysine 27 (H3K27me3) is a chromatin mark that recruits transcriptional repressors, silencing gene transcription. The JmjC family lysine demethylase KDM6B has been identified as an enzyme that removes H3K27me3, allowing for expression of genes critical for brain development. Genetic variants in human KDM6B have been found to be associated with intellectual disability and autism spectrum disorder (ASD); however, the molecular mechanisms by which these genetic variants affect KDM6B function remain unknown. We mapped these variants into the structure of KDM6B, and computationally assessed their likely effects on KDM6B protein function. To experimentally determine how ASD-associated sequence variants in KDM6B affect the function of this protein in cells, we generated ASD-associated mutations into a KDM6B expression construct and assessed their effects on the enzymatic function of this protein as well as its stability and nuclear localization. We found that several ASD-associated mutations occur in the H3K27me3 binding pocket of KDM6B and impair the ability of this enzyme to demethylate histones. In parallel, through RNA sequencing experiments in cerebellar granule neurons from mouse, we found that expression of the enzymatically active form but not the enzymatically dead form of KDM6B was sufficient to rescue synaptic gene expression following knockdown of endogenous KDM6B. Together, these findings elucidate a novel role of KDM6B in controlling gene expression in maturing neurons, and they expand our knowledge on how chromatin dysregulation can lead to neurodevelopmental disorders like ASD.

ORGANISM(S): Mus musculus

PROVIDER: GSE267688 | GEO | 2025/05/14

REPOSITORIES: GEO