Antipsychotic-induced epigenomic reorganization in frontal cortex of individuals with schizophrenia
Genome-wide association studies have revealed >270 loci associated with schizophrenia risk, yet these genetic factors do not seem to be sufficient to fully explain the molecular determinants behind this psychiatric condition. Epigenetic marks such as post-translational histone modifications r...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2024-04-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/92393 |
| _version_ | 1827276433152540672 |
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| author | Bohan Zhu Richard I Ainsworth Zengmiao Wang Zhengzhi Liu Salvador Sierra Chengyu Deng Luis F Callado J Javier Meana Wei Wang Chang Lu Javier González-Maeso |
| author_facet | Bohan Zhu Richard I Ainsworth Zengmiao Wang Zhengzhi Liu Salvador Sierra Chengyu Deng Luis F Callado J Javier Meana Wei Wang Chang Lu Javier González-Maeso |
| author_sort | Bohan Zhu |
| collection | DOAJ |
| description | Genome-wide association studies have revealed >270 loci associated with schizophrenia risk, yet these genetic factors do not seem to be sufficient to fully explain the molecular determinants behind this psychiatric condition. Epigenetic marks such as post-translational histone modifications remain largely plastic during development and adulthood, allowing a dynamic impact of environmental factors, including antipsychotic medications, on access to genes and regulatory elements. However, few studies so far have profiled cell-specific genome-wide histone modifications in postmortem brain samples from schizophrenia subjects, or the effect of antipsychotic treatment on such epigenetic marks. Here, we conducted ChIP-seq analyses focusing on histone marks indicative of active enhancers (H3K27ac) and active promoters (H3K4me3), alongside RNA-seq, using frontal cortex samples from antipsychotic-free (AF) and antipsychotic-treated (AT) individuals with schizophrenia, as well as individually matched controls (n=58). Schizophrenia subjects exhibited thousands of neuronal and non-neuronal epigenetic differences at regions that included several susceptibility genetic loci, such as NRG1, DISC1, and DRD3. By analyzing the AF and AT cohorts separately, we identified schizophrenia-associated alterations in specific transcription factors, their regulatees, and epigenomic and transcriptomic features that were reversed by antipsychotic treatment; as well as those that represented a consequence of antipsychotic medication rather than a hallmark of schizophrenia in postmortem human brain samples. Notably, we also found that the effect of age on epigenomic landscapes was more pronounced in frontal cortex of AT-schizophrenics, as compared to AF-schizophrenics and controls. Together, these data provide important evidence of epigenetic alterations in the frontal cortex of individuals with schizophrenia, and remark for the first time on the impact of age and antipsychotic treatment on chromatin organization. |
| first_indexed | 2024-04-24T06:47:31Z |
| format | Article |
| id | doaj.art-3d93059727454ba289151c44ddd8e836 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-24T06:47:31Z |
| publishDate | 2024-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-3d93059727454ba289151c44ddd8e8362024-04-22T15:24:28ZengeLife Sciences Publications LtdeLife2050-084X2024-04-011210.7554/eLife.92393Antipsychotic-induced epigenomic reorganization in frontal cortex of individuals with schizophreniaBohan Zhu0https://orcid.org/0009-0003-9823-8630Richard I Ainsworth1https://orcid.org/0000-0002-3350-5692Zengmiao Wang2Zhengzhi Liu3Salvador Sierra4Chengyu Deng5Luis F Callado6https://orcid.org/0000-0001-9941-012XJ Javier Meana7https://orcid.org/0000-0002-7913-6714Wei Wang8https://orcid.org/0000-0003-4377-5060Chang Lu9https://orcid.org/0000-0003-0181-5888Javier González-Maeso10https://orcid.org/0000-0003-3105-3204Department of Chemical Engineering, Virginia Tech, Blacksburg, United StatesDepartment of Chemistry and Biochemistry, University of California, San Diego, La Jolla, United StatesDepartment of Chemistry and Biochemistry, University of California, San Diego, La Jolla, United StatesDepartment of Biomedical Engineering and Mechanics, Virginia Tech, Blacksburg, United StatesDepartment of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, United StatesDepartment of Chemical Engineering, Virginia Tech, Blacksburg, United StatesDepartment of Pharmacology, University of the Basque Country UPV/EHU, CIBERSAM, Biocruces Health Research Institute, Bizkaia, SpainDepartment of Pharmacology, University of the Basque Country UPV/EHU, CIBERSAM, Biocruces Health Research Institute, Bizkaia, SpainDepartment of Chemistry and Biochemistry, University of California, San Diego, La Jolla, United States; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United StatesDepartment of Chemical Engineering, Virginia Tech, Blacksburg, United StatesDepartment of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, United StatesGenome-wide association studies have revealed >270 loci associated with schizophrenia risk, yet these genetic factors do not seem to be sufficient to fully explain the molecular determinants behind this psychiatric condition. Epigenetic marks such as post-translational histone modifications remain largely plastic during development and adulthood, allowing a dynamic impact of environmental factors, including antipsychotic medications, on access to genes and regulatory elements. However, few studies so far have profiled cell-specific genome-wide histone modifications in postmortem brain samples from schizophrenia subjects, or the effect of antipsychotic treatment on such epigenetic marks. Here, we conducted ChIP-seq analyses focusing on histone marks indicative of active enhancers (H3K27ac) and active promoters (H3K4me3), alongside RNA-seq, using frontal cortex samples from antipsychotic-free (AF) and antipsychotic-treated (AT) individuals with schizophrenia, as well as individually matched controls (n=58). Schizophrenia subjects exhibited thousands of neuronal and non-neuronal epigenetic differences at regions that included several susceptibility genetic loci, such as NRG1, DISC1, and DRD3. By analyzing the AF and AT cohorts separately, we identified schizophrenia-associated alterations in specific transcription factors, their regulatees, and epigenomic and transcriptomic features that were reversed by antipsychotic treatment; as well as those that represented a consequence of antipsychotic medication rather than a hallmark of schizophrenia in postmortem human brain samples. Notably, we also found that the effect of age on epigenomic landscapes was more pronounced in frontal cortex of AT-schizophrenics, as compared to AF-schizophrenics and controls. Together, these data provide important evidence of epigenetic alterations in the frontal cortex of individuals with schizophrenia, and remark for the first time on the impact of age and antipsychotic treatment on chromatin organization.https://elifesciences.org/articles/92393Schizophreniaepigeneticsantipsychoticsagingpostmortem human brain |
| spellingShingle | Bohan Zhu Richard I Ainsworth Zengmiao Wang Zhengzhi Liu Salvador Sierra Chengyu Deng Luis F Callado J Javier Meana Wei Wang Chang Lu Javier González-Maeso Antipsychotic-induced epigenomic reorganization in frontal cortex of individuals with schizophrenia eLife Schizophrenia epigenetics antipsychotics aging postmortem human brain |
| title | Antipsychotic-induced epigenomic reorganization in frontal cortex of individuals with schizophrenia |
| title_full | Antipsychotic-induced epigenomic reorganization in frontal cortex of individuals with schizophrenia |
| title_fullStr | Antipsychotic-induced epigenomic reorganization in frontal cortex of individuals with schizophrenia |
| title_full_unstemmed | Antipsychotic-induced epigenomic reorganization in frontal cortex of individuals with schizophrenia |
| title_short | Antipsychotic-induced epigenomic reorganization in frontal cortex of individuals with schizophrenia |
| title_sort | antipsychotic induced epigenomic reorganization in frontal cortex of individuals with schizophrenia |
| topic | Schizophrenia epigenetics antipsychotics aging postmortem human brain |
| url | https://elifesciences.org/articles/92393 |
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