Kirill Ulianov1*, Maria Molodova1, Diana Zagirova2, Kirill Morozov1, Polina Morozova3, Olga Efimova4, Sergey Ulianov5, Sergey Razin5, Philipp Khaitovich4 and Ekaterina Khrameeva1
1Center for Bio- and Medical Technologies, Skoltech, Moscow, Russia
2Institute for Information Transmission Problems (the Kharkevich Institute), Russian Academy of Sciences, Moscow, Russia
3Moscow Institute of Psychoanalysis, Moscow, Russia
4Vladimir Zelman Center for Neurobiology and Brain Rehabilitation, Skoltech, Moscow, Russia
5Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia
kirill.ulianov.correspondence [at] gmail.com
Abstract
Schizophrenia is a severe neuropsychiatric disorder affecting cognitive, emotional, and behavioral functions. Despite a long history of research, the genetic basis of schizophrenia remains incompletely understood. The majority of genetic variants associated with schizophrenia risk have small effect sizes and are located in non-coding regions of the genome. Many of these variants are thought to reside within regulatory elements, suggesting that the disorder may involve disturbances of gene regulation. In this context, the regulatory landscape of the genome plays a crucial role in controlling gene activity. Regulatory interactions are strongly constrained by the three-dimensional organization of chromatin. Therefore, studying genome architecture provides an important framework for understanding mental disorders. Here, we investigated chromatin architecture and transcriptomic profiles in schizophrenia.
To obtain information on spatial genome contacts, we applied the Hi-C protocol to postmortem cerebral cortex samples from healthy donors and individuals with schizophrenia. Nuclei were isolated from frozen tissue and separated into neuronal and non-neuronal populations using fluorescence-activated cell sorting. Hi-C libraries were prepared for both populations and subsequently sequenced. In addition to the Hi-C data generated in this study, publicly available RNA-seq datasets from the PsychENCODE consortium were analyzed.
Analysis of Hi-C maps showed that local chromatin structures, including topologically associating domains and chromatin loops, are preserved in schizophrenia. However, analysis of genome-wide contact probability revealed altered age-dependent dynamics of chromatin interactions in neuronal samples of healthy donors. Meanwhile, contact probability did not differ between young and old donors with schizophrenia at any genomic distance. Fluorescence microscopy of cortical sections demonstrated an enlargement of neuronal nuclei in schizophrenia. Transcriptomic analysis indicated aging-related molecular changes in schizophrenia samples. A gene expression-based predictor of chronological age revealed a significant increase in predicted transcriptomic age in schizophrenia compared with controls.
These results indicate that schizophrenia is associated with an enlargement of neuronal nuclei, which may contribute to changes in chromatin interactions. The dynamics of these alterations appear to be age-dependent. Consistent with this observation, transcriptomic analysis also supports the presence of aging-associated processes in schizophrenia.
Keywords: schizophrenia, chromatin, aging
Acknowledgement: This study was supported by the Russian Science Foundation (grant number 25-71-20017).