{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:15:47Z","timestamp":1787008547465,"version":"build-2736575974"},"reference-count":70,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T00:00:00Z","timestamp":1690761600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Eisai-Leonard Wolfson Doctoral Training programme in Neurodegeneration"},{"DOI":"10.13039\/100018231","name":"Aligning Science Across Parkinson\u2019s","doi-asserted-by":"publisher","award":["ASAP 000478"],"award-info":[{"award-number":["ASAP 000478"]}],"id":[{"id":"10.13039\/100018231","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Genetic variants conferring risks for Parkinson\u2019s disease have been highlighted through genome-wide association studies, yet exploration of their specific disease mechanisms is lacking. Two Parkinson\u2019s 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 localizes to the nucleus, where it plays 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\u2019s disease in human brain.<\/jats:p>\n                  <jats:p>Correlation in the expression of non-specific lethal genes and Parkinson\u2019s disease-associated genes was investigated in primary gene co-expression networks using publicly-available transcriptomic data from multiple brain regions (provided by the Genotype-Tissue Expression Consortium and UK Brain Expression Consortium), whilst secondary networks were used to examine cell type specificity. Reverse engineering of gene regulatory networks generated regulons of the complex, which were tested for heritability using stratified linkage disequilibrium score regression. Prioritized gene targets were then validated in vitro using a QuantiGene multiplex assay and publicly-available chromatin immunoprecipitation-sequencing data.<\/jats:p>\n                  <jats:p>Significant clustering of non-specific lethal genes was revealed alongside Parkinson\u2019s disease-associated genes in frontal cortex primary co-expression modules, amongst other brain regions. Both primary and secondary co-expression modules containing these genes were enriched for mainly neuronal cell types. Regulons of the complex contained Parkinson\u2019s disease-associated genes and were enriched for biological pathways genetically linked to disease. When examined in a neuroblastoma cell line, 41% of prioritized gene targets showed significant changes in mRNA expression following KANSL1 or KAT8 perturbation. KANSL1 and H4K8 chromatin immunoprecipitation-sequencing data demonstrated non-specific lethal complex activity at many of these genes.<\/jats:p>\n                  <jats:p>In conclusion, genes encoding the non-specific lethal complex are highly correlated with and regulate genes associated with Parkinson\u2019s disease. Overall, these findings reveal a potentially wider role for this protein complex in regulating genes and pathways implicated in Parkinson\u2019s disease.<\/jats:p>","DOI":"10.1093\/brain\/awad246","type":"journal-article","created":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T09:15:06Z","timestamp":1690794906000},"page":"4974-4987","source":"Crossref","is-referenced-by-count":15,"title":["The non-specific lethal complex regulates genes and pathways genetically linked to Parkinson\u2019s disease"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3965-5253","authenticated-orcid":false,"given":"Amy R","family":"Hicks","sequence":"first","affiliation":[{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology , London WC1N 3BG , UK"},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network , Chevy Chase, MD 20815 , 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