Autism risk gene KMT5B deficiency in prefrontal cortex induces synaptic dysfunction and social deficits via alterations of DNA repair and gene transcription.
Zi-Jun WangBenjamin A ReinPing ZhongJamal WilliamsQing CaoFengwei YangFreddy ZhangKaijie MaZhen YanPublished in: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (2021)
Large-scale genetic screening has identified KMT5B (SUV420H1), which encodes a histone H4 K20 di- and tri-methyltransferase highly expressed in prefrontal cortex (PFC), as a top-ranking high-risk gene for autism. However, the biological function of KMT5B in the brain is poorly characterized, and how KMT5B deficiency is linked to autism remains largely unknown. Here we knocked down Kmt5b in PFC and examined behavioral and electrophysiological changes, as well as underlying molecular mechanisms. Mice with Kmt5b deficiency in PFC display social deficits, a core symptom of autism, without the alteration of other behaviors. Kmt5b deficiency also produces deficits in PFC glutamatergic synaptic transmission, which is accompanied by the reduced synaptic expression of glutamate receptor subunits and associated proteins. Kmt5b deficiency-induced reduction of H4K20me2 impairs 53BP1-mediated DNA repair, leading to the elevation of p53 expression and its target gene Ddit4 (Redd1), which is implicated in synaptic impairment. RNA-sequencing data indicate that Kmt5b deficiency results in the upregulation of genes enriched in cellular stress response and ubiquitin-dependent protein degradation. Collectively, this study has revealed the functional role of Kmt5b in the PFC, and suggests that Kmt5b deficiency could cause autistic phenotypes by inducing synaptic dysfunction and transcriptional aberration.
Keyphrases
- prefrontal cortex
- dna repair
- genome wide
- autism spectrum disorder
- intellectual disability
- dna damage
- poor prognosis
- copy number
- traumatic brain injury
- healthcare
- replacement therapy
- genome wide identification
- oxidative stress
- gene expression
- binding protein
- transcription factor
- mental health
- multiple sclerosis
- dna damage response
- small molecule
- high glucose
- adipose tissue
- skeletal muscle
- endothelial cells
- electronic health record
- genome wide analysis
- cerebral ischemia
- artificial intelligence
- candida albicans
- patient reported
- heat shock protein