From Genetics to Neurodevelopment: Identifying the Role of the Chromatin Regulator KDM5A in Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) is a constellation of neurodevelopmental disorders with high phenotypic and genetic heterogeneity, complicating the discovery of causative genes. Through a forward genetics approach, we identified KDM5A as a candidate ASD gene, regulating vocalization and nest building in mice. We subsequently analyzed whole exome sequencing data from a clinical cohort and identified pathogenic KDM5A variants in patients with ASD. KDM5A encodes a chromatin regulator that belongs to the KDM5 family of lysine-specific histone H3 demethylases. Epigenetic chromatin regulation is essential for establishing and maintaining cellular identity and differentiation. It is required for normal brain development and proper gene expression as well as wiring of neuronal circuits. Disruptions in chromatin regulators lead to several diseases, including ASD. In fact, it is one of the top pathways disrupted in ASD (e.g., ARID1B, CHD8, KMT5B). To characterize the in vivo function of KDM5A, we developed a Kdm5a knockout mouse model (Kdm5a-/-) and showed that loss of KDM5A leads to severe social communication and interaction deficits, repetitive behaviors, and learning and memory deficits. Kdm5a-/- also showed an abnormal neuronal phenotype in the cortex and hippocampus, as well as disruption of transcriptional networks essential for normal brain functions. Patients with ASD in many cases present with cognitive deficits, which are often mediated by the cortex and the hippocampus. These two brain regions are composed of a variety of different cell types, each unique in its functions and transcriptome. However, the specific cell types that are affected in ASD as well as the cell-type specific transcriptional programs that are disrupted in this disease are unknown. To investigate this, we performed single-nuclei RNA sequencing from wildtype (WT) and Kdm5a-/- hippocampal tissue, and single-nuclei RNA and ATAC multiome sequencing from the cortex. We found that KDM5A is essential in establishing hippocampal and cortical cell identity, where specific subtypes of excitatory, inhibitory, and glial cells are disrupted. Our findings advance our knowledge of the role of epigenetic chromatin regulation in dictating cellular identities in the brain and help inform future efforts to develop therapeutic strategies in this genetic subtype of ASD