Accelerated Aging Signatures in 3D Genome Organization and Transcriptome in Schizophrenia
Ulianov, K. A.; Zagirova, D. R.; Kononkova, A. D.; Dudkovskaia, A. V.; Molodova, M. N.; Morozov, K. V.; Efimova, O. I.; Bazarevich, M.; Cherkasov, A. V.; Morozova, P. D.; Tvorogova, A. V.; Pletenev, I. A.; Kondratyev, N.; Golimbet, V. E.; Razin, S. V.; Khaitovich, P. E.; Ulianov, S. V.; Khrameeva, E.
Show abstract
Schizophrenia is a severe neuropsychiatric disorder that affects the behavioral, emotional and cognitive state of patients. Despite its substantial heritability, the molecular etiology of the disease remains poorly understood. Many schizophrenia-associated genetic variants reside in non-coding regions, and exert their effects through distal regulatory elements of the genome. In this context, the three-dimensional organization of the genome is expected to play a decisive role in establishing contacts between these regulatory elements and their target genes, thereby mediating schizophrenia-associated dysregulation of gene expression. Here, we present a novel Hi-C dataset providing an unprecedented view of three-dimensional genome organization in post-mortem schizophrenia brain samples. Our findings indicate that most changes occur at long-range genomic distances while local architecture of topologically-associated domains remains largely intact. However, neurons display localized and functionally relevant loop differences, particularly in regulatory regions associated with neurodevelopmental processes. Global characteristics of higher-order chromatin organization show accelerated aging alteration pattern in schizophrenia, and downstream analysis of transcriptomic data in schizophrenia brain samples further confirms that schizophrenia is associated with accelerated aging.
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