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. 2019 Oct 17;9(1):256.
doi: 10.1038/s41398-019-0596-1.

Chromatin Profiling of Cortical Neurons Identifies Individual Epigenetic Signatures in Schizophrenia

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Free PMC article

Chromatin Profiling of Cortical Neurons Identifies Individual Epigenetic Signatures in Schizophrenia

Fedor E Gusev et al. Transl Psychiatry. .
Free PMC article

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.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. Examples of alterations in chromatin loci in patients with SZ.
In SZ14 group: a the top most commonly upregulated loci for the ncRNA LINC01115 and the novel BNRNA_052780 gene (H3K4me3 peak genomic coordinates are chr2:862857–865643). b The top most commonly downregulated loci for the RP11–678G14.3 gene (peak coordinates are chr19:21768973–21770226) and (c) the novel BNRNA_062360 gene (peak at chr22:37720662–37721774). Examples of rare up and down peaks for (d) FKBP7 (peak at chr2:179342628–179344328), (e) NFATC2IP (peak at chr16:28961457–28963616), (f) HCRTR2 (peak at chr6:55038831–55041158), (g) the intron of HHAT in a single individual with schizophrenia (peak at chr1:210542908–210543238). Examples in SZ2 group: (h) PRKACB (peak at chr1:84629405–84633144), and (i) synaptojanin 2 (SYNJ2; peak at chr6:158401671–158404195). j Quantitative representations of peak sizes for SZ and CTRL groups for the above examples. Samples with SZ are colored in red; control individuals are colored in blue. SZ samples with significant H3K4me3 peaks size change are marked with a star in panels a–i and by dark read in panel j. P-values and fold changes for each SZ sample are presented in Supplementary Tables 4 and 5
Fig. 2
Fig. 2. Analysis of the HLA-DRB9 locus.
a The H3K4me3-marked open chromatin peak at the distal 3′-region of HLA-DRB9 was upregulated in neurons from individuals with schizophrenia (indicated by a star); peak genomic coordinates are chr6:32427120–32428371. b The transcription activity(Illumina BodyMap 2.0 data) and chromatin state suggest common activity of this locus in the testis. c A cluster of significant variations from GWAS data for schizophrenia next to the peak (18). The log Y-scale represents reported nominal P-values for variants (36,989 cases and 113,075 controls). Bottom panel: the SNPs rs9268830 (inside the peak) and rs9268895 (the most significant SNP associated with schizophrenia in GWAS data) (19). SZ samples are marked with S prefix, control individuals are marked with C prefix. Red and blue colors indicate SZ and CTRL, respectively
Fig. 3
Fig. 3. Putative looping interactions in the HLA-DRB9 locus.
a Schematic representation of genes near the peak and putative looping interactions between SZ peak, SNP rs9268895, and nearby genes BTNL2, HLA-DRB9, and HLA-DRB5. b 3C experimental analysis of cells from postmortem cortical tissues revealed at least four looping interactions. SZ schizophrenia; CON control; -L no ligase
Fig. 4
Fig. 4. Top 10 enriched gene ontology terms analyzed with ConsensusPathDB for the SZ14 group.
Terms with FDR-adjusted P-values of less than 0.01 are highlighted in green

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References

    1. Insel TR. Rethinking schizophrenia. Nature. 2010;468:187–193. doi: 10.1038/nature09552. - DOI - PubMed
    1. De Jong S, et al. Expression QTL analysis of top loci from GWAS meta-analysis highlights additional schizophrenia candidate genes. Eur. J. Hum. Genet. 2012;20:1004–1008. doi: 10.1038/ejhg.2012.38. - DOI - PMC - PubMed
    1. Kirov G, et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol. Psychiatry. 2012;17:142–153. doi: 10.1038/mp.2011.154. - DOI - PMC - PubMed
    1. Guha S, et al. Implication of a rare deletion at distal 16p11.2 in schizophrenia. JAMA Psychiatry. 2013;70:253–260. doi: 10.1001/2013.jamapsychiatry.71. - DOI - PMC - PubMed
    1. Purcell SM, et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature. 2014;506:185–190. doi: 10.1038/nature12975. - DOI - PMC - PubMed

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