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The non-specific lethal complex regulates genes and pathways genetically linked to Parkinson’s disease
Published July 30, 2023
Output Details
Preprint July 31, 2023
Published July 30, 2023
Description
Article published in Brain on 31 July 2023. Initial Preprint doi: 10.1101/2023.01.16.523926 / https://doi.org/10.1101/2023.01.16.523926 posted on 18 January 2023.
Two Parkinson's disease candidate genes, KAT8 and KANSL1, identified through genome-wide studies and a PINK1-mitophagy screen, encode part of the histone acetylating non-specific lethal complex. This complex localises to the nucleus, where it has a role in transcriptional activation, and to mitochondria, where it has been suggested to have a role in mitochondrial transcription. In this study, we sought to identify whether the non-specific lethal complex has potential regulatory relationships with other genes associated with Parkinson's disease in human brain. Significant clustering of non-specific lethal genes was revealed alongside Parkinson's disease-associated genes in frontal cortex primary co-expression modules. Both primary and secondary co-expression modules containing these genes were enriched for mainly neuronal cell types. Regulons of the complex contained Parkinsons disease-associated genes and were enriched for biological pathways genetically linked to disease. When examined in a neuroblastoma cell line, 41% of prioritised gene targets showed significant changes in mRNA expression following KANSL1 or KAT8 perturbation. In conclusion, genes encoding the non-specific lethal complex are highly correlated with and regulate genes associated with Parkinson's disease. Overall, these findings reveal a potentially wider role for this protein complex in regulating genes and pathways implicated in Parkinson's disease.
Identifier (DOI)
10.1093/brain/awad246