Chromatin profiling of cortical neurons identifies individual epigenetic signatures in schizophrenia

Fedor E. Gusev, Denis A. Reshetov, Amanda C. Mitchell, Tatiana V. Andreeva, Aslihan Dincer, Anastasia P. Grigorenko, Gennady Fedonin, Tobias Halene, Maria Aliseychik, Elena Filippova, Zhiping Weng, Schahram Akbarian, Evgeny I. Rogaev

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Both heritability and environment contribute to risk for schizophrenia. However, the molecular mechanisms of interactions between genetic and non-genetic factors remain unclear. Epigenetic regulation of neuronal genome may be a presumable mechanism in pathogenesis of schizophrenia. Here, we performed analysis of open chromatin landscape of gene promoters in prefrontal cortical (PFC) neurons from schizophrenic patients. We cataloged cell-type-based epigenetic signals of transcriptional start sites (TSS) marked by histone H3-K4 trimethylation (H3K4me3) across the genome in PFC from multiple schizophrenia subjects and age-matched control individuals. One of the top-ranked chromatin alterations was found in the major histocompatibility (MHC) locus on chromosome 6 highlighting the overlap between genetic and epigenetic risk factors in schizophrenia. The chromosome conformation capture (3C) analysis in human brain cells revealed the architecture of multipoint chromatin interactions between the schizophrenia-associated genetic and epigenetic polymorphic sites and distantly located HLA-DRB5 and BTNL2 genes. In addition, schizophrenia-specific chromatin modifications in neurons were particularly prominent for non-coding RNA genes, including an uncharacterized LINC01115 gene and recently identified BNRNA_052780. Notably, protein-coding genes with altered epigenetic state in schizophrenia are enriched for oxidative stress and cell motility pathways. Our results imply the rare individual epigenetic alterations in brain neurons are involved in the pathogenesis of schizophrenia.

Original languageEnglish
Article number256
JournalTranslational Psychiatry
Volume9
Issue number1
DOIs
StatePublished - 1 Dec 2019

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